Drug dispenser

ABSTRACT

There is provided a drug dispenser device comprising a housing defining a first chamber; extending from said housing and defining a second open chamber, an outlet for insertion into a body cavity of a patient; provided to said first chamber of the housing, a discharge block defining a discharge block orifice; receivable within the first chamber for movement therewithin, a drug discharge device, said drug discharge device having a longitudinal axis and comprising a container for storing a drug formulation to be dispensed, a discharge mechanism and a discharge channel from said container, wherein said discharge channel is receivable by said discharge block to enable discharge of said drug formulation via said discharge block orifice to said outlet; provided to the housing; and at least one finger operable member moveable to apply a force directly or indirectly to the drug discharge device for movement along the longitudinal axis towards the discharge block to actuate said discharge mechanism. The housing further defines an aperture through which said at least one finger operable member in part protrudes, and wherein the at least one finger operable member is moveable from a rest position in which the at least one finger operable member acts to block off said aperture to an actuating position in which the aperture is unblocked and through which air may be drawn into the housing in response to patient inhalation through the outlet.

The present application is filed pursuant to 35 USC 371 as a UnitedStates National Phase Application of International Patent ApplicationSerial NO. PCT/EP2007/058676 filed on 21 Aug. 2007, which claimspriority from U.S. Provisional Application No. 60/823,141, filed 22 Aug.2006, incorporated herein by reference in its entirety.

The disclosures of the following U.S. Provisional Applications are alsoincorporated herein by reference in their entirety: U.S. ProvisionalApplication Nos. 60/823,134, 60/823,139, 60/823,143, 60/823,146,60/823,151 and 60/823,154, all filed on 22 Aug. 2006; U.S. ProvisionalApplication No. 60/894,537 filed on 13 Mar. 2007; and U.S. ProvisionalApplication No. 60/956,947 entitled DRUG DISPENSER and U.S. ProvisionalApplication No. 60/956,950 entitled DRUG DISPENSER simultaneously filedherewith,

The disclosures of the International (PCT). Patent Applicationssimultaneously filed herewith which designate the United States ofAmerica and claim priority from the aforementioned U.S. ProvisionalApplication Nos. 60/823,134 60/823,139 60/823,143, 60/823,146,60/823,151 and 60/523,154, are all also incorporated herein by referencein their entirety:

The present invention relates to a drug dispenser and in particular to adrug dispenser for delivering metered doses of aerosol or fluid drugformulation and adapted for use as an oral or nasal inhaler.

It is known to provide an actuator for an inhaler (e.g. a metered doseinhaler (MDI)) for delivering drug by inhalation, which actuatorcomprises a housing arranged for receipt of a container that containsdrug formulation to be dispensed. The container typically comprises abody, which includes a base and a head, and a discharge mechanism (e.g.a valve or pump) which extends from the body and from which drug is inuse discharged upon actuation thereof. The actuator also comprises anoutlet, which is arranged for receipt by the mouth or nose of a user andthrough which a user in use inhales. The actuator further comprises adischarge assembly, which provides for delivery of drug through theoutlet, wherein the discharge assembly typically comprises a dischargeblock, which receives the discharge mechanism of the container.

It is also known to provide an inhaler, in which a drug dose isdispensed to the patient via an outlet upon the application of a forceby a user to an actuating lever or similar finger operable memberprovided to the housing. Typically, displacement of the actuating leveris arranged to transfer actuating force to the discharge mechanismprovided to the drug container, which results in discharge of a drugdose. Such inhalers may be arranged to dispense a single dose or mayalternatively be arranged with a reservoir containing several doses tobe dispensed.

In conventional metered dose inhalers (MDIs) the housing is generallyopen to the environment. Typically, the base of the drug canister isarranged to protrude from an opening provided at the top of theactuator. This arrangement is designed to facilitate user access to thebase of the canister for actuation of the inhaler by a user's finger andthumb motion which results in depression of the canister against adischarge block of the actuator housing and hence, firing thereof.

Applicant realizes that where an inhaler is instead arranged foractuation in response to user-applied force to an actuating lever orsimilar finger operable member provided to the housing it is notnecessary that the housing is generally open to the environment. Indeed,it is considered advantageous from a hygiene standpoint to ‘close off’from the environment that part of the housing, which generally housesthe drug container and discharge assembly. This generally ‘closed off’form can minimize undesirable ingress of foreign bodies (e.g. dirtparticles), which might otherwise contaminate those working parts housedwithin the now ‘closed off’ housing.

For effective operation of the inhaler it is desirable that one or moreair inlets be provided to the housing, which air inlets allow air to bedrawn into the housing (and desirably past the discharge mechanism ofthe container and discharge assembly) in response to the patientinhalation through an outlet (e.g. mouthpiece or nosepiece) of theinhaler. For optimal hygiene such air passage into the housing shouldonly be enabled during use of the device and otherwise, the housingremains generally ‘closed off’ from the environment.

Applicant therefore proposes an inhaler housing, in which is defined anaperture through which an actuating lever or other finger operablemember at least in part protrudes. The finger operable member ismoveable from a rest position in which the finger operable member actsto block off that aperture to an actuating position in which theaperture is unblocked and through which air may be drawn into thehousing in response to patient inhalation through the outlet. Thus, bothhygiene and effective operability requirements are provided for.

It is an aim of this invention to provide a drug dispenser that providesfor effective operability and hygienic storage of a drug containerthereof.

According to a first aspect of the invention there is provided a drugdispenser device according to claim 1 hereof.

There is provided a drug dispenser device for dispensing of a drugformulation to a patient by the inhaled route.

The drug dispenser device comprises a housing, which defines a firstchamber and which is suitable for wholly or partly housing some or allof the parts of the dispenser device. The housing may have any suitableform but is suitably sized and shaped for ready accommodation by thehand of a patient. In particular, the housing is sized and shaped toenable one-handed operation of the dispenser device.

In preferred embodiments, the first chamber of the housing isessentially ‘closed off’ other than for the (i) the discharge orifice ofthe discharge block, which allows for flow of discharged drug (e.g.aerolised form) from the discharge channel of the drug discharge deviceto the second chamber and thence to the outlet; and/or (ii) at least onefurther opening between the first chamber and second chamber to allowfor air flow therebetween in response to patient inhalation through theoutlet; and (iii) the selectively blocked off aperture, through whichthe at least one finger operable member protrudes. This generally‘closed off’ form of the first chamber is desirable from the standpointof minimizing undesirable ingress of foreign bodies (e.g. dirt particlesand other debris), which might otherwise contaminate the working partsof the drug dispenser device housed within the first chamber.

Extending from the housing and defining a second open chamber, there isprovided an outlet for insertion into a body cavity of a patient. Wherethe patient body cavity is the mouth of a patient, the outlet isgenerally shaped to define a mouthpiece. Where the patient body cavityis the nose of a patient, the outlet is generally shaped in nozzle formfor receipt by a nostril of the patient. Thus, the part of the outlet,which allows for dispensed drug and/or air flow to the mouth or nose ofthe patient, also defines the principal opening of the ‘open’ form ofthe second chamber.

In embodiments, the outlet includes at least one air flow path whichprovides for a substantially annular air flow at an inner peripheralsurface of the outlet on inhalation by the patient through the outlet,such as to provide a sheathing air flow to discharged drug (e.g.aerosolised form) when delivered from the discharge block orifice. Inembodiments, a circular arrangement of plural air flow paths isprovided.

In embodiments, the outlet is provided with a removeable protectivecover such as a mouthpiece cover or nozzle cover.

Provided to the first chamber of the housing, there is a discharge blockdefining a discharge block orifice.

In embodiments, the discharge block comprises, as a separately-formedcomponent, a discharge outlet which fluidly connects to the dischargeblock orifice of the discharge block and includes a discharge outletorifice from which drug is in use, delivered.

The discharge outlet is in embodiments, integrally formed with orcoupled to the outlet. In embodiments, the outlet comprises an externalsection which is configured to be gripped in the lips of the user anddefines an open end through which drug is in use delivered and aninternal section which defines a rear section to which the dischargeoutlet couples.

In embodiments, at least a rear section of the discharge outlet has anincreasing internal dimension in a direction away from the dischargeblock. In one embodiment, the discharge outlet defines an essentiallycone-shaped interior. In another embodiment, the discharge outletdefines an essentially an essentially bucket-shaped interior.

In embodiments, the discharge block includes a laterally-directed cavitywhich receives the discharge outlet. In embodiments, the dischargeoutlet is captively disposed in the laterally-directed cavity. Thedischarge outlet is suitably held captive in the laterally-directedcavity by any suitable joining or sealing method such as by use of apress-fit or snap-fit method; by use of a clip engaging mechanism; byuse of over-welding; or by use of heat-staking. In embodiments, thedischarge outlet is a snap-fit in the laterally-directed cavity.

In embodiments, the laterally-directed cavity includes a recess and thedischarge outlet includes a projection which is captively engaged in therecess. In embodiments, the discharge outlet is an interference fit inthe laterally-directed cavity.

In embodiments, the discharge outlet includes a delivery channel whichis fluidly connected to the discharge outlet orifice and narrows towardsthe same. In one embodiment, the delivery channel has arcuate wallsections. In another embodiment, the delivery channel has substantiallystraight wall sections.

In embodiments, a sheathing air flow path at the outlet is enabled bythe provision of air inlets to the discharge outlet. Where the dischargeoutlet is essentially bucket-shaped it has been found to be preferablethat the air inlets are provided to the base of the bucket.

In embodiments, the annular air flow is in a direction away from thedischarge block orifice. In embodiments, the outlet includes a pluralityof air flow paths which together provide for the substantially annularair flow at the inner peripheral surface of the outlet.

Receivable within the first chamber and movement within the firstchamber, there is provided, a drug discharge device. In embodiments, thedrug discharge device is enclosed by the housing (i.e. enclosed withinthe first chamber). The drug discharge device has a longitudinal axisand comprises a container for storing a drug formulation to bedispensed. In embodiments, the container adopts a generally cylindricalform and the longitudinal axis is defined by the central axis of thecylinder. The container is suitably arranged to have a neck at one end.

The container is provided with a discharge mechanism, which communicateswith a discharge channel extending from the container. The dischargechannel is receivable by the discharge block to enable discharge of saiddrug formulation via the discharge block orifice to the outlet. Inembodiments, the discharge channel extends out from a neck of thecontainer.

Typically, the discharge mechanism is provided with spring mechanism (orother biasing mechanism) that provides a degree of bias that must beovercome in order to allow discharge of drug from the dischargemechanism. Typically, that spring mechanism also acts as a returnmechanism to assist with return the discharge mechanism to its reststate after firing thereof.

It will be appreciated that the shape and form of the discharge channelwill be matched to that of the discharge block for effective receiptthereby. In embodiments, the discharge channel is received by a cavityor passage provided to the discharge block of the housing, which cavityor passage enables communication with the discharge block orifice andthence with the outlet for dispensing of discharged drug to a patient.

In one aspect, where the discharge channel is the valve stem of a valvedaerosol canister, the valve stem is received within a discharge block inthe form of a stem block provided to the housing, which stem blockincludes a passage which acts such as to channel discharged aerosolizeddrug from the valve stem to the outlet.

In another aspect, where the discharge channel is the discharge tube ofa fluid pump discharge device, the discharge tube is received within adischarge block in the form of a discharge tube block provided to thehousing, which discharge tube block includes a passage which acts suchas to guide discharged fluid drug from the discharge tube to the outlet.

In one aspect, the drug discharge device is suitable for dispensingaerosolized drug and thus, generally comprises an aerosol canisterprovided with a discharge valve of the type well-known for use inmetered dose inhaler (MDI) type drug dispensers. The canister isgenerally formed of metal (e.g. aluminium). The valve generally includesa return spring such that once the valve has been fired it is returnedto an ‘at rest’ position ready for subsequent firing thereof.

In a metered dose inhaler (MDI) the discharge device is for dispensingdrug in aerosol form, wherein the drug is comprised in an aerosolcontainer suitable for containing a propellant-based aerosol drugformulation. The aerosol container is typically provided with a meteringvalve, for example a slide valve, which acts as the discharge mechanismfor release of the aerosol form drug formulation to the patient. Theaerosol container is generally designed to deliver a predetermined doseof drug upon each actuation by means of the valve, which can be openedby compressing the valved aerosol container, for instance by depressingthe valve while the container is held stationary or by depressing thecontainer while the valve is held stationary.

Where the drug container is an aerosol container, the valve typicallycomprises a valve body having an inlet port through which a drug aerosolformulation may enter said valve body, an outlet port through which theaerosol may exit the valve body and an open/close mechanism by means ofwhich flow through said outlet port is controllable.

The valve may be a slide valve wherein the open/close mechanismcomprises a sealing ring and receivable by the sealing ring a valve stemhaving a dispensing passage, the valve stem being slidably movablewithin the ring from a valve-closed to a valve-open position in whichthe interior of the valve body is in communication with the exterior ofthe valve body via the dispensing passage.

Typically, the valve is a metering valve. The metering volumes aretypically from 10 to 100 μl, such as 25 μl, 50 μl or 63 μl. Inembodiments, the valve body defines a metering chamber for metering anamount of drug formulation and an open/close mechanism by means of whichthe flow through the inlet port to the metering chamber is controllable.In preferred embodiments, the valve body has a sampling chamber incommunication with the metering chamber via a second inlet port, saidinlet port being controllable by means of an open/close mechanismthereby regulating the flow of drug formulation into the meteringchamber.

The valve may also comprise a ‘free flow aerosol valve’ having a chamberand a valve stem extending into the chamber and movable relative to thechamber between dispensing and non-dispensing positions. The valve stemhas a configuration and the chamber has an internal configuration suchthat a metered volume is defined therebetween and such that duringmovement between its non-dispensing and dispensing positions the valvestem sequentially: (i) allows free flow of aerosol formulation into thechamber, (ii) defines a closed metered volume for pressurized aerosolformulation between the external surface of the valve stem and internalsurface of the chamber, and (iii) moves with the closed metered volumewithin the chamber without decreasing the volume of the closed meteredvolume until the metered volume communicates with an outlet passagethereby allowing dispensing of the metered volume of pressurized aerosolformulation.

Suitably any of the inner parts of the valve (e.g. those which in use,will contact the drug formulation) are coated with material (e.g.fluoropolymer material) that reduces the tendency of drug to adherethereto. Suitable fluoropolymer materials includepolytetrafluoroethylene (PTFE) and fluoroethylene propylene (FEP). Anymovable parts may also have coatings applied thereto, which enhancetheir desired movement characteristics. Frictional coatings maytherefore be applied to enhance frictional contact and lubricants usedto reduce frictional contact as necessary.

In another aspect, the drug discharge device is a fluid discharge devicesuitable for dispensing of fluid drug formulation (e.g.non-pressurised/propellant-free) and thus, generally comprises a fluidcontainer provided with a compression pump. Such pumped dischargedevices are most commonly used in dispensers for dispensing fluid formdrug for nasal delivery.

A suitable fluid discharge device comprises a container for storing afluid to be dispensed having a neck at one end, a compression pumphaving a suction inlet located within the container and a discharge tubeextending out from the neck of the container for transferring said fluidfrom the pump. The pump generally includes a return spring such thatonce the pump has been fired it is returned to an ‘at rest’ positionready for subsequent firing thereof.

A suitable pre-compression pump would be a VP3, VP7 or modifications,model manufactured by Valois SA. Typically, such pre-compression pumpsare typically used with a bottle (glass or plastic) container capable ofholding 8-50 ml of a formulation. Each spray will typically deliver50-100 μl of such a formulation and the device is therefore capable ofproviding at least 100 metered doses.

There is provided to the housing, at least one finger operable membermoveable to apply a force directly or indirectly to the drug dischargedevice for movement of the drug discharge device along the longitudinalaxis towards the discharge block to actuate the discharge mechanism. Inpreferred embodiments, the at least one finger operable member ismoveable transversely with respect to the longitudinal axis of the drugdischarge device.

The at least one finger operable member may be arranged to apply a forceeither directly or indirectly to the drug discharge device for actuationthereof. Where force is applied directly, a portion of the at least onefinger operable member suitably engages the base of the container of thedrug discharge device to push the container down in actuating fashion.Described hereinafter are other mechanisms including stored energymechanisms, in which force is applied indirectly to the drug dischargedevice through one or more actuating mechanism parts.

The term at least one finger operable member is meant to encompass suchmembers operable by action of the finger or thumb, or combinationsthereof of a typical user (e.g. an adult or child patient). Inembodiments, at least part of the at least one finger operable member isergonomically shaped to assist interaction of the patient's fingerand/or thumb therewith. Thus, in embodiments the at least one fingeroperable member may be shaped for ease of patient finger or thumbcontact and/or be provided with surface features and/or other detailingthat facilitates the desired interaction.

In embodiments, the at least one finger operable member is arranged toapply mechanical advantage. That is to say, the at least one fingeroperable member applies mechanical advantage to the user force to adjust(generally, to enhance or smooth) the force experienced by the transferelement. The mechanical advantage may in one aspect, be provided ineither a uniform manner such as by a constant mechanical advantageenhancement, for example by a ratio of from 1.5:1 to 10:1 (enhancedforce:initial force), more typically from 2:1 to 5:1. In another aspect,the mechanical advantage is applied in a non-constant manner such asprogressive increase or progressive decrease of mechanical advantageover the applied force cycle. The exact profile of mechanical advantagevariation may be readily determined by reference to the desireddispensing performance of the dispenser device.

In embodiments, the at least one finger operable member has a form,which naturally gives rise to mechanical advantage such as a lever.

In preferred embodiments, the at least one finger operable membercomprises of at least one lever pivotally connected to part of thehousing and arranged to urge the discharge device towards the dischargeblock when the or each lever is moved by a user.

In one preferred aspect, there are two opposing levers, each of whichpivotally connect to part of the housing and may be arranged to transferforce directly or indirectly to the drug discharge device for movementof the drug discharge device along the longitudinal axis when the twolevers are squeezed together by a user.

In one aspect, the movement of the two opposing levers is coupled, whichcoupling acts to wholly or partly compensate for uneven force beingapplied in use, by a patient to one lever as applied to the other lever.Any suitable coupling mechanism may be employed. In one aspect, the twoopposing levers are provided with meshing teeth, which teeth arearranged to mesh together thereby providing a coupling action. Suchcoupling provides the further advantage when the opposing levers areactuated (e.g. by squeezing together) an equivalent-sized opening isunblocked (i.e. opened-up) about either lever, thereby providing formore even (i.e. symmetric) airflow through the device when a patientinhales therethrough.

In embodiments, the or each lever is pivotally supported at a lower endwithin the housing. By ‘at a lower end within the housing’ it isgenerally meant at that end of the housing which in normal use of thedrug dispenser device by a patient is lowermost. The use of a lower endpivoted lever configuration has the advantage that a long lever can beused thereby maximising the mechanical ratio between the input force andthe force applied to actuate the drug discharge device. In addition theuse of a lever pivotally supported at its lower end is ergonomicallymore efficient than using a lever pivotally supported at an upper enddue to the fact that a user will normally grasp the dispenser devicewith their thumb positioned close to the end of the lever. With a leverpivotally supported at an upper end (again, relative to the normal inuse′ configuration) the location of a patient's thumb is close to theposition about which the lever pivots and hence the maximum leverage isnot obtained.

The housing further defines an aperture through which the at least onefinger operable member at least in part protrudes, thereby making the atleast one finger operable member accessible for finger/thumb actuationby a user. The protruding part of the at least one finger operablemember is suitably shaped for finger and/or thumb interaction and maythus be provided with friction and/or gripping features to facilitatefinger/thumb interaction.

Where more than one finger operable member (e.g. plural levers) ispresent, each is typically associated with an aperture through which atleast part of that finger operable member protrudes. In embodiments, theor each aperture for the or each finger operable member is the sole(intended) entry point for airflow into the housing on patientinhalation at the outlet.

The at least one finger operable member is moveable from a rest positionin which the at least one finger operable member acts to block off saidaperture to an actuating position in which the aperture is unblocked andthrough which air may be drawn into the housing in response to patientinhalation through the outlet.

In the rest position, the aperture is blocked off. By ‘blocked off’ itis meant that the aperture is essentially closed, particularly with theintention of blocking accessing to foreign bodies (e.g. dirt particlesand other debris). An air-tight seal does not need to be formed,although in preferred embodiments the degree of blocking off issufficient to at least impede or restrict air flow therethrough. Inembodiments, a small gap (e.g. 0.5 mm all round) exists between theaperture of the housing and the at least one finger operable member.Desirably, in the rest position, the at least one finger operable memberand the housing do not ‘pinch’ or ‘jam’ together. Such ‘pinching’ or‘jamming’ interaction could otherwise affect the finger/thumb assistedmovement of the at least one finger operable member which is requiredfor operation of the device.

In embodiments, the at least one finger operable member is biasedtowards its resting position (i.e. with apertures blocked off) by asuitable biasing mechanism provided to the dispenser device. Inembodiments the biasing mechanism is provided as (e.g. ‘doubles up’ as)a component of an actuating mechanism for actuating the container.

In the actuating position, the aperture is unblocked and air may thus,be drawn into the housing (i.e. the first chamber thereof and thence, toother parts thereof) in response to patient inhalation through theoutlet.

In embodiments, the actuation mechanism for actuating the drug dispenserdevice herein comprises:

(f) connecting to the container, a container collar that engages thecontainer;

(g) connecting to said container collar and moveable with respectthereto along the longitudinal axis of the drug discharge device, atransfer element, said transfer element including an actuating portion,wherein the at least one finger operable member is moveable to apply aforce to said actuating portion of said transfer element to move thetransfer element along the longitudinal axis in a first direction;(h) connecting the container collar with the transfer element, a biasingmechanism to store biasing energy on moving the transfer element alongthe longitudinal axis in the first direction; and(i) provided to the container collar, a pre-load mechanism to preventtransfer of said biasing energy to the container collar to move saidcontainer along the longitudinal axis in the first direction to actuatethe discharge mechanism until a pre-determined threshold force isovercome.

In embodiments, there is provided connecting to the container, acontainer collar that engages the container. The container collar istherefore suitably in essentially fixed relationship with (i.e. it fixesto) the container. In embodiments, the container collar engages (e.g. inessentially fixed relationship) with a neck of the container.

The container collar may engage with the (e.g. neck of the) container byany suitable means of permanent or temporary engagement including asnap-fit engagement mechanism. Preferably, as in the illustratedembodiments hereinafter, the container collar is permanently connectedto the container through use of a split-ring collar as described in U.S.patent application Ser. No. 10/110,611 (WO-A-01/28887) andUS-A-2006/0082039.

In embodiments, the at least one finger operable member is arranged fordirect engagement with the container collar to apply actuating force tothe container collar to push or pull the container down in actuatingfashion.

In other embodiments, there is further provided connecting (via abiasing mechanism as later described) to the container collar andmoveable with respect thereto along the longitudinal axis of the drugdischarge device, a transfer element. The transfer element may have anysuitable form but preferably comprises an extension collar that is sizedand shaped for receipt by the container and arranged in suitable fashionrelative to the container collar. In one aspect, the extension collar issized and shaped for receipt around (i.e. external to) the containercollar.

In these other embodiments, the transfer element includes an actuatingportion and the at least one finger operable member is moveable to applya force to the actuating portion of the transfer element to move thetransfer element along the longitudinal axis in the first direction. Theactuating portion is shaped for interaction with the at least one fingeroperable member, and may take any form that facilitates and accommodatesthat interaction including abutment (e.g. flange or shelf), rack andpinion gear and indent forms. In embodiments, the actuating portiondefines an abutment surface. Similarly, the at least one finger operablemember is suitably shaped for direct interaction with the actuatingportion, and may take any form that facilitates and accommodates thatdirect interaction including abutment and indent forms. In embodiments,the at least one finger operable member defines a cam surface arrangedfor interaction with the actuating portion of the transfer element.

Optionally, there is provided to drug dispenser device a lockingmechanism for reversibly locking/unlocking the movement of the at leastone finger operable member and/or any container collar. The purpose ofthe locking mechanism is to prevent unintended movement of the at leastone finger operable member and/or container collar and hence, to preventunintended actuation of the dispenser device.

In embodiments, the locking mechanism comprises a locking elementcomprising any suitable limb, protrusion, or abutment which acts such asto interfere with the unintended movement of the at least one fingeroperable member and/or container collar. Such unintended movement mayfor example, arise as a result of patient misuse of the dispenser deviceor during transport of the device (e.g. when carried in the pocket orbag of a patient).

In one aspect, the locking mechanism is provided to a removeable coverfor the outlet (e.g. mouthpiece or nozzle cover). Thus, in use thepatient would remove the outlet cover thereby simultaneously revealingthe outlet and unlocking the locking mechanism. Conversely, after theuse the outlet cover is replaced to again lock the at least one fingeroperable member and/or container collar. In alternative aspects, thelocking mechanism may comprise an integral part of the removeable coveror by provided as a fixed add-on thereto or be provided as a moveable(e.g. rotatable or translatable) add-on thereto.

In one aspect, the locking mechanism is arranged to prevent unintendedmovement of the container collar and hence, firing of the dischargemechanism, but does not impede the movement of the at least one fingeroperable member and/or of the transfer element. Thus, when the containercollar is in its locked state (i.e. the locking mechanism is performingits locking function) the at least one finger operable member (e.g.levers) may still be moved and that movement transfer energy via thebiasing mechanism to move the transfer element, but all movement of thecontainer collar is prevented. This form of locking arrangement has theadvantage that unintended force applied to the finger-operable (e.g.levers) allows for travel thereof without damage thereto or to thedevice as a whole, but without any actuation of the dispenser device(e.g. by firing of the discharge mechanism).

In embodiments, the container collar is provided at its underside withone or more (e.g. two) downward protrusions and the mouthpiece isprovided with a locking mechanism in the form of one or moreinterference elements. In embodiments, the interference element(s) isP-shaped and joined to the mouthpiece by means of a suitable hinge (e.g.living hinge) about which the interference element(s) may rotate. In anembodiment, there are two interference elements joined together by abridge element. When, the mouthpiece engages with the body of thedispenser device (i.e. in the mouthpiece-closed position) theinterference element(s) abuts the downward protrusion(s) to therebyprevent (i.e. lock) any downward movement of the container collar.Unintended movement of the container collar and hence, unintendedactuation of the dispenser device (i.e. firing of the dischargemechanism) is hence prevented. In embodiments, however the at least onefinger operable member and transfer element are free to move, even whenthe container collar is in its locked state.

One particular locking mechanism, in which one or more rotatableinterference elements are provided to the mouthpiece, is described inApplicant's co-pending PCT Patent Application No. WO-A-2007/028,992which claims priority from UK patent application no. 0518355, eachincorporated herein by reference.

In embodiments, there is further provided a biasing mechanism which actssuch as connect the container collar to the transfer element. Thebiasing mechanism acts to store biasing energy on moving the transferelement relative to the container collar along the longitudinal axis inthe first direction.

In embodiments, the biasing mechanism comprises one or more springs orother resiliently compressible or expandable mechanical members forstoring mechanical energy.

In preferred embodiments of this type, the biasing mechanism comprisesan arrangement of two springs locating one on either side of thecontainer collar (i.e. 180° radial spacing).

The Applicant realizes that for effective actuation of the dischargemechanism (e.g. valve or pump) of the drug discharge device any biasingmechanism should be capable of storing (and releasing) sufficientbiasing energy to both overcome any pre-determined force of any pre-loadmechanism and to actuate that discharge mechanism. Thus, for examplewhere the discharge mechanism comprises a valve or pump having a returnspring, the biasing mechanism should be capable of providing sufficientbiasing energy to overcome that return spring to reliably fire the valveor pump.

The Applicant realizes that it is desirable that the actuating force,which is applied by the patient to the at least one finger operablemember be kept to a minimum. Desirably also, the overall size of thedevice is kept relatively small (e.g. fits comfortably in the patient'shand) from both an ergonomics and aesthetics standpoint. Desirably also,the dispenser device is made of plastic components, although this bringswith it the challenge that the mechanical strength of certain plasticsreduces with time, particularly if they are left in a tensed state.

Thus, in embodiments the biasing mechanism is suitably arranged toprovide an initial high biasing tension (e.g. to be equal to or greaterthan the force required to actuate a return spring of the valve or pump,but necessarily also less than that of a pre-determined threshold forceof any pre-load mechanism), and further to have a low spring rate (i.e.the tension therein increase by only a low rate as the biasing mechanismis moved in response to user-actuation of the at least one fingeroperable member). Applicant realizes that it can be difficult to achievethis with a compression spring since it would require making a springwith a low spring rate then compressing it a given distance to achievethe initial high biasing tension, and then assembling it into thedevice. It would therefore always be putting a load upon any plasticcomponents of the device.

Thus, in embodiments the biasing mechanism comprises one or moreextension springs.

In embodiments, the degree of extension of the or each extension springis greater than that of the degree of spring extension required toovercome any return spring (e.g. valve or pump return spring) of thedischarge mechanism to fire that discharge mechanism.

In preferred embodiments, the extension springs have a closed coil form,which suitably defines an initial biasing tension in its ‘at rest’state. In embodiments, that initial biasing tension provided by the oneor more extension springs in combination is just below (e.g. from 1 to15N, such as from 3 to 10N below) that of the pre-determined thresholdforce of the pre-load mechanism.

In embodiments, the one or more extension springs define a low springrate. That is to say extension thereof does not require undue user forceto be applied. This is advantageous in that extension thereof inresponse to user actuation of the at least one finger operable memberdoes not thereby, put undue strain on the user. In embodiments, thespring rate of the or each extension spring is in the range from 0.5 to5 N/mm, such as from 1 to 3 N/mm.

In embodiments, there is further provided to the container collar, apre-load mechanism to prevent transfer of biasing energy to thecontainer collar to move said container along the longitudinal axis inthe first direction to actuate the discharge mechanism until apre-determined threshold force is overcome.

Thus, initially as the transfer element moves along the longitudinalaxis in response to patient actuation of the at least one fingeroperable member the spacing (along the longitudinal axis) between thetransfer element and the container collar (which does not move)increases and biasing energy builds up in the biasing mechanism. Oncehowever, the pre-determined threshold force as defined by the pre-loadmechanism is exceeded, the biasing energy is released and the containercollar is thereby, drawn along the longitudinal axis and in the firstdirection, which action results in actuation of the discharge mechanismresulting in discharge of drug formulation through the discharge channeland to the outlet for delivery to the patient.

In other words, the pre-load mechanism acts such as to prevent actuationof the discharge mechanism of the drug discharge device until apre-determined threshold force is applied to the at least one fingeroperable member. The pre-determined threshold force may thus, be thoughtof as a ‘barrier’ force which must first be overcome before the energystored in the biasing mechanism may be released to actuate the dischargemechanism. In essence, the pre-load mechanism acts as a ‘commitment’feature, which allows release of actuating energy to the dispensingmechanism only when the ‘barrier’ force has been exceeded.

The quantum of pre-determined force that is to be overcome beforeactuation of the discharge mechanism is enabled is selected according tovarious factors including the typical user profile, nature of the drugformulation and the desired discharge characteristics.

Typically, the pre-determined threshold force is in the range from 5 to40N, more typically from 10 to 30N (e.g. 15N). That is to say, typicallyfrom 5 to 40N, more typically from 10 to 30N (e.g. 15N) of force must beapplied to overcome the pre-determined threshold before actuation of thedischarge mechanism is enabled. Such values tend to correspond to aforce which prevents a suitable ‘barrier force’ to a weak, nondescriptor unintended finger movement whilst readily being overcome by thedetermined finger (or thumb) action of a user. It will be appreciatedthat if the device is designed for use by a child or elderly patient itmay have a lower pre-determined force than that designed for adultusage.

In embodiments, the pre-load mechanism is interposed between thecontainer collar and the housing.

In embodiments, the pre-load mechanism comprises one or more detentsformed on the container collar for engagement with part of the housing,the or all of the detents being disengageable from the housing when thepre-determined threshold force is applied to the transfer element viathe at least one finger operable member so as to allow the containercollar to move along the longitudinal axis in such a way that thedischarge mechanism is actuated.

In preferred embodiments, each detent comprises a flexible (e.g.resilient) support limb, such as a support leg, which engages (e.g.latches to) a step or abutment provided to the housing. When thepre-determined threshold force is overcome, the or each flexible supportlimb disengages from the step or abutment to allow the container collarto move along the longitudinal axis such that the discharge mechanism isactuated. In embodiments, the or each support limb is provided to thelower end of the container collar (i.e. that end which is closest to theoutlet). An arrangement of from two to four (e.g. three) flexiblesupport limbs is particularly preferred. Alternatively, the or eachsupport limb may have a hinged or articulated form.

In embodiments, a guide mechanism is provided to the transfer element(e.g. extension collar) to guide the disengagement of the flexiblesupport limb from its respective step or abutment on the housing.Preferably, such guide mechanism comprises a guide ramp, which interactswith a shaped head of each flexible support limb.

In embodiments, a reseat guide mechanism is provided to the transferelement (e.g. extension collar) to guide the re-engagement of theflexible support limb with its respective step or abutment on thehousing. Preferably, such reseat guide mechanism comprises a reseatguide ramp, which interacts with a shaped reseat head of each flexiblesupport limb.

In embodiments the ‘disengagement’ guide mechanism (e.g.) ramp interactswith an outer shaped head of each flexible support limb and the‘re-engagement’ reseat guide mechanism (e.g. ramp) interacts with aninner shaped reseat head of each flexible support limb.

Alternatively, the pre-load mechanism may comprise of one or moredetents formed on the housing for engagement with part of the containercollar, the or all of the detents being disengageable from the containercollar when the pre-determined threshold force is applied to thetransfer element via the at least one finger operable member so as toallow the discharge mechanism to be actuated.

In embodiments, the drug dispenser herein includes an actuation counter.The actuation counter suitably includes a mechanism for registering anddisplaying dose count information to the patient. In embodiments, thatdose count information relates to the number of doses of drug deliveredfrom or remaining in the dispenser device. The information may bedelayed in digital or analogue form, typically using standard countindicia (e.g. ‘999’ to ‘000’ indicia count display). Embodimentsinvolving either ‘counting up’ or ‘counting down’ in increments areenvisaged.

The pre-load mechanism herein acts such as prevent transfer of biasingenergy to the container collar to actuate the actuation counter until apre-determined threshold force is overcome. Thus, a count is registeredby the actuation counter only in response to a user actuation that issufficient to overcome the ‘barrier’ force provided by the pre-loadmechanism and which thereby results in dispensing of a dose from thedrug container.

In embodiments, the actuation counter is actuable in response tomovement of the container collar or of the container along thelongitudinal axis in the first direction.

In embodiments, the actuation counter is actuable in response to drive(e.g. engageable drive) interaction with a driver element provided tothe container collar or container. The driver element may for example,take the form of a protrusion (e.g. tooth), an abutment, an indent or aslot provided to the container collar or container.

In embodiments, the actuation counter is actuable in response to driveinteraction with a driver element provided to a drive feature connectingto the container collar or container. The driver element may forexample, take the form of a protrusion (e.g. tooth), an abutment, anindent or a slot provided to the drive feature. In embodiments, thedrive feature comprises a plate connecting to the container collar.

The actuation counter may adopt any suitable form. The actuation counteris in embodiments sized and shaped for effective receipt by the housingof the drug dispenser. In embodiments, the actuation counter has theform described in Applicant's co-pending U.S. Provisional ApplicationNo. 60/894,537 filed on 13 Mar. 2007 or in U.S. Provisional ApplicationNo. 60/956,947 entitled DRUG DISPENSER commonly owned and filedsimultaneously herewith, both incorporated herein by reference in theirentirety.

Embodiments are envisaged in which the drug discharge device isreversibly removable from the housing of the drug dispenser device. Insuch embodiments the drug dispenser device comprises a housing assemblyand a drug discharge device receivable thereby.

According to a still further aspect of the present invention there isprovided a kit of parts comprising a housing assembly as described aboveand a drug discharge device receivable thereby.

It is also envisaged that the housing assembly could be supplied as aseparate item, into which a user or pharmacist later fits a suitabledrug discharge device.

The drug dispenser device of the invention is suitably an inhaler, moresuitably of the well-known “metered dose inhaler” (MDI) type, and yetmore suitably a hand-held, hand-operable breath-coordinated MDI. In sucha MDI, the patient manually actuates the MDI for release of the drugfrom the drug discharge device while concurrently inhaling at theoutlet. Thus inhalation and actuation are coordinated. This is indistinction from breath-operated MDIs, where the inhalation event itselfactuates the MDI so that no coordination is required.

Additional aspects and features of the present invention are set forthin the claims and in the description of exemplary embodiments of thepresent invention which now follow with reference to the accompanyingFigures of drawings. Such exemplary embodiments may or may not bepracticed mutually exclusive of each other, whereby each embodiment mayincorporate one or more features of one or more of the otherembodiments. It should be appreciated that the exemplary embodiments areset forth to illustrate the invention, and that the invention is notlimited to these embodiments.

The invention will now be described further with reference to theaccompanying drawing in which:—

FIG. 1 shows a perspective view of a hand-held, hand-operable, breathcoordinated drug dispenser device of the MDI type herein in the ‘atrest’ position;

FIG. 2 shows a perspective view of the drug dispenser device of FIG. 1with upper front cover part, actuation counter, front plate, mouthpieceand mouthpiece cover removed and the lower front cover part shown incut-away section, the device again being shown in the ‘at rest’position;

FIGS. 3a to 3b show front views of the drug dispenser device of FIG. 1with upper front cover part, actuation counter, front plate andmouthpiece cover removed and the left lower front cover part andleft-side of mouthpiece shown in cut-away section, the devicerespectively being shown in ‘at rest’ and first stage of actuationpositions;

FIGS. 4a to 4c show front views of the drug dispenser device of FIG. 1with upper front cover part, actuation counter, front plate, mouthpiececover and left lever removed and the left lower front cover part andleft-side of mouthpiece shown in cut-away section, the devicerespectively being shown in second, third and fourth stages of actuationpositions;

FIG. 5 shows an exploded view from the front of part of the internalmechanism of the drug dispenser device of FIG. 1 with front plateremoved;

FIG. 6 shows a schematic view of part of the internal mechanism of thedrug dispenser device of FIG. 1 with front plate removed, and inparticular, the ‘interlock’ mechanism provided to block actuationthereof when the mouthpiece is covered by the mouthpiece cover;

FIG. 7 shows a perspective view of the drug dispenser device of FIG. 1with the mouthpiece cover removed from the mouthpiece and thus, in a‘ready to use’ position;

FIG. 8 shows a perspective view of the drug dispenser device of FIG. 1with the mouthpiece cover removed from the mouthpiece and the leversdepressed and thus in the ‘in use’ position;

FIG. 9 illustrates a perspective view of a first half of the drugdispenser of FIG. 1 showing air flow into the housing in the ‘in use’position thereof;

FIG. 10 illustrates a perspective cut-away view of a second half of thedrug dispenser device of FIG. 1 (with actuation counter and details ofinternal mechanism omitted) showing air flow through the chambers of thehousing in the ‘in use’ position thereof;

FIG. 11 illustrates a perspective cut-away view of a second half of adrug dispenser device that is a slight variation of that drug dispenserdevice of FIG. 1 (with actuation counter and details of internalmechanism omitted) showing air flow through the inhaler body in the inuse′ position thereof;

FIG. 12 shows an exploded view of an actuation counter herein arrangedfor receipt within the front upper housing part of the first drugdispenser of FIG. 1 or second drug dispenser device of FIG. 11;

FIGS. 13a and 13b respectively show underside and top views of theactuation counter of FIG. 1;

FIGS. 14a and 14b show cut-away views of the actuation counter of FIG.12 at respectively ‘count 120’ and ‘count 119’ positions;

FIGS. 15a and 15b respectively show cut-away views corresponding toFIGS. 14a and 14b of the actuation counter of FIG. 12 absent thedecimals count wheel;

FIGS. 16a and 16b respectively show cut-away views corresponding toFIGS. 14a and 14b of the actuation counter of FIG. 12 absent thenumerals count wheel;

FIGS. 17a and 17b show cut-away views of the actuation counter of FIG.12 at respectively ‘count_0’ and ‘shuttered’ positions;

FIGS. 18a and 18b respectively show cut-away views corresponding toFIGS. 17a and 17b of the actuation counter of FIG. 12 absent thenumerals count wheel;

FIG. 19 shows a front view of the drug dispenser device of FIG. 1 withupper front cover part and actuation counter removed, the device beingin the ‘at rest’ position;

FIG. 20 shows a perspective view of the drug dispenser device of FIG. 1with the upper front cover part and actuation counter disposed thereinshown detached from the remainder of the device, the device being shownin a ‘at rest’ position;

FIG. 21 shows a plan view of the inner side of the upper front coverpart of the drug dispenser device of FIG. 1 and showing the actuationcounter disposed therein;

FIGS. 22 and 23 show perspective views of a container collar part foruse in an alternative internal mechanism for use with the drug dispenserdevice herein, as respectively shown in upright and invertedconfigurations;

FIGS. 24 and 25 respectively show perspective underside and top views ofan extension collar part for use in an alternative internal mechanismfor use with the drug dispenser device herein;

FIGS. 26a to 26c show perspective views of sequential steps in theassembly of an alternative internal mechanism for use with the drugdispenser device herein, and employing the container collar of FIGS. 22and 23 and the extension collar of FIGS. 24 and 25;

FIGS. 27a to 27c show sectional side views of interaction of key partsof the container collar of FIGS. 22 and 23 with the extension collar ofFIGS. 24 and 25 during sequential operational steps of the alternativemechanism assembled as shown in FIGS. 26a to 26 c;

FIG. 28 shows a perspective view from above of the lower housing partand mouthpiece assembly (shown separated) of the drug dispenser deviceof FIG. 1;

FIGS. 29a and 29b show an alternative two part form′ lower housing part,as respectively shown separated and as assembled, for use with the drugdispenser device of FIG. 1; and

FIGS. 30a to 30n respectively show front views of mouthpiece forms,which may be employed in the drug dispenser devices of FIG. 1 or 11 asan alternative to the mouthpieces thereof.

Turning now to the drawings, FIG. 1 shows a drug dispenser device 1herein which is in the form of a hand-held, hand-operable, breathcoordinated pressurised metered dose inhaler (MDI). This type of devicerequires a patient to coordinate their inhalation at a dispensing outletof the device (in this embodiment, a mouthpiece 14) with manualactuation of the device so that the inhalation is coordinated withrelease of drug from the device so that drug is entrained by theinhalation airflow to the target location in the respiratory tract (inthis case, the lungs) of the patient.

The device 1 comprises a housing defined in combination by front 10 aand rear 10 b upper housing parts and lower housing part 12, all ofwhich are, in this embodiment, formed from plastic. It will be notedthat the overall form of the housing is arranged for ease of receipt bya user's hand such that in general terms the rear of lower housing part12 is received by the user's palm. Mouthpiece 14 (not visible in FIG. 1,but see FIG. 3a ) is protected by removeable mouthpiece cover 16, andextends from the front of lower housing part 12 and is arranged in use,for insertion into the mouth of a patient for inhalation therethrough.

A ledge 13 a, 13 b is provided to the base of the lower housing part 12such that the device may be arranged to ‘stand upright’ on the ledges 13a, 13 b and mouthpiece cover 16, when cover 16 covers the mouthpiece 14.As will be understood from FIG. 7, when the cover 16 is moved to its‘mouthpiece uncovered’ position, the device is able to ‘stand upright’on the end face 16 a of the cover 16 itself.

A viewing window 216 is provided to the front upper housing part 10 afor viewing of count indicia displayed by a counter 201 locating withinthat part 10 a and described in more detail hereinafter with referenceto FIGS. 12 to 21.

Opposing levers 20 a, 20 b protrude from apertures 11 a, 11 b providedto the front 10 a and rear 10 b upper housing parts. The levers 20 a, 20b are shaped such as to respectively accommodate the finger and thumb ofa patient in use, thereby facilitating one-handed operation of thedevice.

FIG. 28 shows the lower housing part 12 and mouthpiece 14 (shownseparated from each other, in this view) of the drug dispenser device ofFIG. 1. Provided to the lower housing part 12 is stem block 8, which isarranged to receive valve stem 7 of an aerosol canister 5 (see also FIG.2). The stem block 8 also includes a passage 9, which in use acts suchas to guide discharged aerosolized drug from the valve stem 7 to themouthpiece 14. Step portions 18 a, 18 b, 18 c, the purpose of which willbe described in more detail in the later description, are also provided.

FIGS. 29a and 29b show an alternative two part form′ lower housing part412, as respectively shown separated and as assembled, for use with thedrug dispenser device of FIG. 1 as an alternative to the lower housingpart 12 of FIG. 28. This two part form comprises lower housing part 412,which is arranged to receive separate stem block part 490. That separatestem block part 490 includes stem block 408 and stem block passage 409.As before, the lower housing part defines step portions 418 a, 418 b,418 c. During assembly the separate parts 412, 490 are brought togetherand sockets 494 a, 494 b, 494 c on the stem block part 490 aligned withposts 492 a, 492 b, 492 c on the lower housing part. The parts 412, 490are then joined to each other by means of heat welding (‘heat staking’)at each respective post 492 a, 492 b, 492 c to socket 494 a, 494 b, 494c mating point. Advantages of using the alternative ‘two part form’lower housing part 412 and stem block part 490 assembly are that theprecision features of the stem block part 490 are easier to produce andinspect. The stem block part 490 is generally made from a polymerselected for ease of drug delivery. The lower housing part 412 is inembodiments, formed of ABS.

Details of the inner workings of the device 1 of FIG. 1 may beappreciated by reference to FIG. 2, in which the upper 10 a fronthousing part and mouthpiece cover 16 have been removed. It will be seenthat each opposing lever 20 a, 20 b pivotally connects to the upperhousing part 10 a, 10 b by means of pivot connector 22 a, 22 b. Thepositioning of the pivotal connection is selected to facilitate thedesired finger-thumb operability of the levers 20 a, 20 b by a squeezingmovement. It will also be seen that the lower ends 21 a, 21 b of eachlever 20 a, 20 b mesh together, thereby tending to the couple the motionof each respective lever 20 a, 20 b one to the other.

Although not shown, each lever 20 a, 20 b has a lower end 21 a, 21 b oneither side thereof providing a generally U-shape to each lever 20 a, 20b.

Provided to the housing, but largely obscured from view by containercollar 30, there is provided a drug discharge device, which takes theform of cylindrical valved aerosol canister 5 of the type commonly knownfor use in an MDI. A valve stem 7 of the drug discharge device isreceived within a stem block 8 provided to the housing, which stem block8 includes a passage 9 which acts such as to guide dischargedaerosolized drug from the valve stem to the mouthpiece 14.

The levers 20 a, 20 b are arranged in the device such that the lowerends 21 a, 21 b of each lever 20 a, 20 b are disposed on opposing sides(front and rear) of the drug discharge device.

In this particular embodiment, and referring to FIG. 5, the canister 5has a body 6 made of metal, for instance of stainless steel or, morepreferably, of aluminium or an aluminium alloy. The canister contains apressurised drug aerosol formulation. The formulation comprises the drug(one or more drug actives) and a fluid propellant, and optionally one ormore excipients and/or adjuvants. The drug is in solution or suspensionin the formulation. The propellant is typically a CFC-free propellant,suitably a liquid propellant, and preferably is a HFA propellant, suchas HFA-134a or HFA-227 or a combination thereof. The drug active(s) istypically of the type for use in treatment of a respiratory disease orcondition, such as asthma or chronic obstructive pulmonary disease(COPD). The active(s) may also be for prophylaxis or palliation of arespiratory disease or condition.

The canister 5 may have its inner surface coated with a fluorocarbonpolymer, optionally in a blend with a non-fluorocarbon polymer, such asa blend of polytetrafluoroethylene and polyethersulphone (PTFE-PES), asdisclosed in U.S. Pat. Nos. 6,143,277; 6,511,653; 6,253,762; 6,532,955;and 6,546,928. This is particularly preferred if the drug is insuspension in the formulation, and especially if the suspensionformulation is composed only, or substantially only, of the drug and HFApropellant.

The valve stem 7 forms part of a metering valve (not shown) mounted inthe canister 5, as will be understood by the skilled person in the art,and as commercially available from manufacturers well known in theaerosol industry, for example, from Valois, France (e.g. DF10, DF30,DF60), Bespak plc, UK (e.g. BK300, BK356, BK357) and 3M-Neotechnic Ltd,UK (e.g. Spraymiser™). The metering chamber of the metering valve may becoated with a fluorinated polymer coating, such as formed fromperfluoro-hexane, for instance by cold plasma polymerisation, asdetailed in US-A-2003/0101993.

As may be further understood with reference also to FIG. 5, which showsan exploded view of key parts of the internal mechanism, the containercollar 30 permanently engages via split-ring collar 33 with the neck 5 aof the canister 5 such that the so-engaged parts are moveable togetherrelative to the housing in a direction defined by the longitudinal axisL-L of the canister 5 (i.e. generally up and down when the device 1 isupright). The split-ring collar 33 permanently engages the containercollar 30 to the canister 5 as described in U.S. patent application Ser.No. 10/110,611 (WO-A-01/28887) and US-A-2006/0082039.

The container collar 30 connects via closed coil extension springs 50 a,50 b and respective spring connection points 31 a, 31 b and 41 a, 41 bto extension collar 40, which is provided at its lower end with a ramp44. This multi-collar arrangement is such that the extension collar 40is moveable with respect to the container collar 30 along thelongitudinal axis L-L of the drug discharge device.

The springs 50 a, 50 b will typically be formed of metal, for instancestainless steel, such as 302 grade stainless steel.

As shown in FIG. 5, the extension collar 40 includes an actuatingportion, in the form of shelf 42, on opposing sides which are arrangedfor interaction with the lower ends 21 a, 21 b of the opposing levers 20a, 20 b such that when the levers are squeezed together (i.e. inwardsrelative to the housing) the shelf 42 and hence, extension collar 40 arepushed downwards. The container collar 30 is further provided withflexible support legs 34 a, 34 b each of which is provided with aprotruding foot 35 a, 35 b for latching engagement with a respectivestep 18 a, 18 b provided to the housing (see FIG. 2). Each leg 34 a, 34b also has a shaped head 36 a, 36 b the purpose of which will becomeclearer from the later description.

In the ‘at rest’ position of FIGS. 2 and 3 a, each foot 35 a, 35 b isslightly spaced from its respective step 18 a, 18 b on the housing. Athird flexible support leg (not visible, but associated with third step18 c as visible on FIG. 28) locates at the rear of the container collar(i.e. there are three flexible support legs 34 a, 34 b). In oneembodiment, the two support legs 34 a, 34 b on either side of themouthpiece 14 are spaced at 113.4° intervals relative to a third supportleg (not visible) which locates rearwards to the mouthpiece 14.

The container collar 30 is further provided with downward protrusions 38a, 38 b, the purpose of which will become clear from the laterdescription.

In general operational terms, referring now also to FIG. 3a , theopposing levers 20 a, 20 b are moveable transversely with respect to thelongitudinal axis L-L of the drug discharge device to apply a force tothe shelf 42 of the extension collar 40 to move the extension collar 40downwards along that longitudinal axis (i.e. towards stem block 8 andmouthpiece 14).

The closed coil extension springs 50 a, 50 b that connect the containercollar 30 via connector points 31 a, 31 b with the extension collar 40act as a biasing mechanism to store biasing energy on moving theextension collar 40 downwards along the longitudinal axis L-L inresponse to squeezing of the levers 20 a, 20 b. In embodiments, aninitial biasing tension—inherent in the closed coil form thereof—ispresent in the closed coil extension springs 50 a, 50 b even when intheir ‘at rest’ state.

The flexible support legs 34 a, 34 b act to provide a pre-load mechanismto prevent transfer of that biasing energy to the container collar 30 tomove the canister 5 downwards along the longitudinal axis L-L to actuatethe valve thereof (and hence, to fire the aerosolized drug dose) until apre-determined threshold force is overcome.

Further details of the operation of the device 1 (which results from aneffective user actuation thereof) may be appreciated by making referenceto FIGS. 3a to 4c , in which for clarity only selected parts relevant tothe particular stage of operation represented are labelled.

FIG. 3a shows how the device 1 is configured in the ‘at rest’ position,in this instance also with the mouthpiece 14 covered by the mouthpiececover 16. The levers 20 a, 20 b are splayed apart and catch retainers 24a, 24 b provided to an inner part of the protruding end 23 a, 23 b ofeach respective lever 20 a, 20 b locate close to ‘stop’ positionsdefined by notches 15 a, 15 b provided to the top parts 10 a, 10 b ofthe housing. The lower ends 21 a, 21 b of each lever 20 a, 20 b seatagainst the shelf 42 of the extension collar 40 but no force acts on theextension collar 40. The closed coil extension springs 50 a, 50 b aretherefore in their ‘at rest’ state with no externally-applied (i.e. bylever 20 a, 20 b actuation) biasing energy stored therein (but only anyinitial biasing tension—inherent in the closed coil form of theextension springs 50 a, 50 b—present). Each foot 35 a, 35 b of theflexible support legs 34 a, 34 b is slightly spaced from its respectivestep 18 a, 18 b on the housing.

In FIG. 3b , the device is shown at a first early stage of operation,after removal of the mouthpiece cover 16 from the mouthpiece 14, inwhich the levers 20 a, 20 b have been squeezed very slightly together.The lower ends 21 a, 21 b of each lever 20 a, 20 b push slightly down onthe shelf 42 of the extension collar 40 such that the extension collar40 is moved slightly downwards. That downwards movement of the extensioncollar 40 is transferred via the extension springs 50 a, 50 b to thecontainer collar 30, which also moves slightly downwards. Importantly,this downwards movement of the container collar 30 brings each foot 35a, 35 b of the flexible support legs 34 a, 34 b into latching engagementwith its respective step 18 a, 18 b on the housing. As a result of thislatching engagement, further downwards movement of the container collar30 is impeded.

In FIG. 4a , the device is shown at a second stage of operation, inwhich the levers 20 a, 20 b have been squeezed further together. Thelower ends 21 a, 21 b of each lever 20 a, 20 b push further down on theshelf 42 of the extension collar 40 such that the extension collar 40 ismoved downwards. That downwards movement of the extension collar 40however, cannot now be transferred via the extension springs 50 a, 50 bto the container collar 30 because of the latching engagement of eachfoot 35 a, 35 b of the flexible support legs 34 a, 34 b with itsrespective step 18 a, 18 b on the housing. That latching engagementimpedes the downwards movement of the container collar 30. The downwardsmovement of the extension collar 40 therefore results in the extendingof each closed coil extension spring 50 a, 50 b, thereby resulting inbiasing energy being stored in the now-extended springs 50 a, 50 b.

In FIG. 4b , the device is shown at a third stage of operation, in whichthe levers 20 a, 20 b have been squeezed even further together. Thelower ends 21 a, 21 b of each lever 20 a, 20 b push even further down onthe shelf 42 of the extension collar 40 such that the extension collar40 is moved even further downwards. That further downwards movement ofthe extension collar 40 still cannot now be transferred via theextension springs 50 a, 50 b to the container collar 30 because of thelatching engagement of each foot 35 a, 35 b of the flexible support legs34 a, 34 b with its respective step 18 a, 18 b on the housing. Thefurther downwards movement of the extension collar 40 therefore resultsin further extension of each extension spring 50 a, 50 b, therebyresulting in further biasing energy being stored in the nowwell-extended springs 50 a, 50 b.

Further, in the position shown in FIG. 4b , ramps 44 provided to theextension collar 40 respectively engage with the shaped heads 36 a, 36 bof the flexible legs 34 a, 34 b and act on the already-tensed flexiblelegs 34 a, 34 b such that each foot thereof 35 a, 35 b is at the pointof becoming displaced from its respective step 18 a, 18 b. In essence,the ramp 44 acts to ‘guide’ the displacement action. Thus, FIG. 4bcorresponds to the position at which the pre-load threshold force(typically about 16N) provided by the latching engagement of theflexible legs 34 a, 34 b with their steps 18 a, 18 b is just about to beovercome by the biasing energy stored in the extension springs 50 a, 50b. This position therefore corresponds to the threshold (or ‘tippingpoint’) of the pre-load/stored biasing energy system defined by thecomponents of the device. Applying any further squeeze force to thelevers 20 a, 20 b will result in that threshold being exceeded, andeffective user actuation of the device 1.

In FIG. 4c , which corresponds to a fourth stage of operation, suchfurther force has been applied to the levers 20 a, 20 b. The protrudingend 23 a, 23 b (see also FIG. 3a ) of each respective lever 20 a, 20 btouches off one against the other, thereby preventing any further lever20 a, 20 b travel. Most importantly, the flexible legs 34 a, 34 b havebecome displaced from their respective steps 18 a, 18 b through theaction of the ramps 44. The container collar 30 may now move freelydownwards and indeed, will do so as a result of its experience of thebiasing energy stored in the extension springs 50 a, 50 b. The containercollar 30 and canister 5 in permanent engagement therewith move rapidlydownwards propelled by the stored biasing energy of the springs 50 a, 50b. The valve of the canister 5 is thereby activated to releaseaerosolized drug through the passage 9 in the stem block 8 which guidesthat discharged aerosolized drug to the mouthpiece 14 for inhalation bythe patient.

It will be appreciated that once the threshold force has been overcome(i.e. just past the ‘tipping point’ of the device) a uniform actuatingforce resulting from the energy stored in the springs 50 a, 50 b isexperienced by the container collar 30 and canister 5 regardless of howmuch extra force is applied by the patient to the levers 20 a, 20 b. Aconsistent actuation of the valve of the canister 5 is thereby, enabledby the configuration of the device 1.

Following actuation, the coiled coil extension springs 50 a, 50 b returnto their ‘at rest’ state (i.e. with no externally-applied biasingenergy, but only any initial biasing tension inherent in the closed coilform of the extension springs 50 a, 50 b present). As will beappreciated by the skilled reader in the art, the return spring (notshown) of the valve of the valved canister provides energy to move thecanister 5, container collar 30, extension collar 40 and levers 20 a, 20b back to the ‘at rest’ position as shown in FIG. 2. Further actuatingoperations may therefore be conducted until the canister 5 is exhaustedof its drug formulation contents.

FIG. 6 shows a particular detail of the first drug dispenser device ofFIGS. 1 to 5. For succinctness, only those parts relevant to this detailare now described further.

As previously described, the container collar 30 is provided at itsunderside with two downward protrusions 38 a, 38 b. The mouthpiece cover16 is further provided with P-shaped cam interference elements 17 a, 17b joined together by bridge element 18 and joining to the mouthpiececover 16 by means of living hinge 19 about which the bridgedinterference elements 17 a, 17 b may pivot. When, as shown in FIG. 6,the mouthpiece cover 16 engages with the body 12 of the dispenser device1 to close the mouthpiece 14 (i.e. in the mouthpiece-closed position)the interference elements 17 a, 17 b adopt a position in which theylocate underneath the downward protrusions 38 a, 38 b in close proximityor abutment therewith to thereby prevent any downward movement of thecontainer collar 30. See also FIG. 3a . Unintended movement of thecontainer collar 30 and hence, unintended actuation of the dispenserdevice 1 is hence prevented.

In a subtle point, it is noted that when the mouthpiece cover 16 is inplace such that the interference elements 17 a, 17 b prevent thedownward movement of the container collar 30 the levers 20 a, 20 b;extension springs 50 a, 50 b; and extension collar 40 are not locked andare therefore free to move. The levers 20 a, 20 b may thus, still becompressed to the point at which their protruding ends 23 a, 23 b touchoff, but without any movement of the container collar 30 and actuationof the dispenser device 1. When the protruding ends 23 a, 23 b are sotouched off the user will also not be able to apply further, potentiallydamaging, force to the interference elements 17 a, 17 b or to the stemblock 8.

The relative positioning of the interference elements 17 a, 17 b and thecollar protrusions 38 a, 38 b in the various stages of operation of thedevice 1 is shown in FIGS. 3 and 4. FIG. 3a shows the spatialrelationship when the mouthpiece cover 16 is in the mouthpiece-closedposition, whilst FIGS. 3b and 4a-4c show the spatial relationship withthe cover 16 removed and the levers being depressed inwardly to fire thedevice 1.

The mouthpiece cover 16 may take one of the particular forms describedin PCT Patent Application No. WO-A-2007/028992, which claims priorityfrom UK patent application No. 0 518 355 filed 8 Sep. 2005, the entirecontent of which applications, and any subsequent US (PCT) patentapplication, are incorporated herein by reference.

FIGS. 7 to 10 illustrate aspects of the air flow into and through thehousing of the drug dispenser device of FIG. 1 during use thereof. Forsuccinctness, only those parts of the drug dispenser relevant to theseaspects are now described.

FIG. 7 shows the drug dispenser device 1 of FIG. 1 in a ‘ready to use’position with the mouthpiece cover 16 removed from the mouthpiece 14. Itwill be noted that in this position, the mouthpiece cover 16 is pivotedto a position underneath the lower housing part 12. The opposing levers20 a, 20 b, which protrude from apertures 11 a, 11 b provided to thefront 10 a and rear 10 b upper housing parts, are in their restposition. It will also be noted that in this position, the opposinglevers 20 a, 20 b act to block off the apertures 11 a, 11 b such as toprevent ingress of dirt particles or other debris into the body of thedevice 1.

FIG. 8 shows the drug dispenser device 1 of FIG. 1 in the ‘in use’position, in which the opposing levers 20 a, 20 b have been movedtowards each other, typically in response to a patient finger and thumbsqueezing action. In this position, the opposing levers 20 a, 20 b nolonger act to block off the apertures 11 a, 11 b such that air 60 a, 60b may flow through the opened up apertures 11 a, 11 b into the upperhousing part 10 a, 10 b in response to patient inhalation 61 through themouthpiece 14.

The air flow ‘in use’ through the device 1 is now described in moredetail with reference to FIGS. 9 and 10.

FIG. 9 shows one half of the device 1 of FIG. 1 in the ‘in use’position, in which the mouthpiece 14 is revealed, and in which lever 20b has been pushed inwards to open up aperture 11 b. External air 60 bmay thus, now be drawn into the body of the device housing through thisaperture 11 b (and also similarly through aperture 11 a on the otherside) in response to patient inhalation through the mouthpiece 14. Inother words, the patient coordinates their inhalation at the mouthpiece14 to depression of the levers 20 a, 20 b so that the resulting airflowthrough the housing 10 a, 10 b, which enters via the opened apertures 11a, 11 b and exits through the mouthpiece 14, is coincident with therelease of the drug from the canister 5 caused through actuation of thelevers 20 a, 20 b. The airflow thus entrains the drug into therespiratory tract of the patient.

FIG. 10 illustrates in more detail, the air flow 60 a, 62 through thebody of the device 1 during use thereof (i.e. again with the device 1 inthe ‘in use’ position of FIGS. 8 and 9).

Referring to FIG. 10 in more detail, the device 1 may be seen tocomprise a discharge assembly in the form of a stem block assembly 3which is integrally formed with the lower body part 12 and provides forthe delivery of an aerosol spray of a drug on actuation of the inhaler.Mouthpiece 14 is a separately formed part which is fitted to the lowerbody part 12 (as shown in FIG. 28) and in use is gripped in the lips ofthe user to facilitate oral inhalation. Received within the an enclosedchamber defined by the housing parts 10 a, 10 b, 12 there is providedaerosol canister 5 which contains drug to be delivered on actuation ofthe inhaler and is fitted in the main body and fluidly connected to thestem block assembly 3.

The mouthpiece 14 comprises an external section 15 which is configuredto be gripped in the lips of a subject and defines a substantiallycylindrical, open forward end through which an aerosol spray of a drugis in use delivered on actuation of the inhaler, an essentially‘bucket-shaped’ open chamber form internal section 17 which has a closedrear section (other than air holes 66 and spray orifice 72 describedhereinafter), and a discharge outlet in the form of a nozzle outlet 70which is coupled to a rear end of the internal section 17, such as toprovide for the delivery of an aerosol spray 64 into and through theinternal section 17.

In response to patient inhalation, air 60 a is drawn down the rear part10 b of the body of the device 1 past around the stem block assembly 3and towards the rear of the internal section 17 of the mouthpiece 14,which is provided with a duality of slot-like air holes 66 at the rear(i.e. base of the ‘bucket’) thereof arranged about spray orifice 72. Theair holes 66 may be equi-spaced from the spray orifice 72. As may beseen, when the air 60 a is drawn through these dual air holes 66 aduality of air flows 62 is defined within the mouthpiece 14. Thisprovides for a partly annular air flow at the inner peripheral surfaceof the mouthpiece 14, which partly sheaths the aerosol spray 64 asdelivered from the spray orifice 72 of the nozzle outlet 70, therebypartly entraining the aerosol spray 64 and reducing deposition at theinternal surface of the mouthpiece 14.

In this embodiment the rear of the internal section 17 has a generallyflat shape, which forms the base of the ‘bucket’. The edges of the basecurve outwards such that the internal section 17 has an increasinginternal dimension in a direction away from the stem block assembly 3.

The nozzle outlet 70 includes the spray orifice 72 which provides forthe delivery of an aerosol spray through the internal section 17 of themouthpiece 14 and a delivery channel 74 which fluidly connects thedelivery passage 9 of the stem block assembly 3 to the spray orifice 72.

In this embodiment the delivery channel 74 is a tapering channel whichnarrows towards the spray orifice 74. In this embodiment the deliverychannel 74 has straight wall sections.

In this embodiment, the stem block assembly 3 comprises the stem block 8for receiving the valve stem 7 of the canister 5, and the nozzle outlet70 of the mouthpiece 14 which is fluidly connected to the stem block 8,such as to provide for the delivery of an aerosol spray through themouthpiece 14. The stem block 8 may be integrally formed with the lowerbody part 12.

The stem block 8 includes a tubular bore 76 for receiving the valve stem7 of the canister 5, which in this embodiment is co-axial with thelongitudinal axis H-H of the housing (FIG. 3a ), which housing axis H-Hin this embodiment is coincident with the longitudinal axis L-L of thedrug delivery device when mounted in the drug dispenser device 1. Thetubular bore 76 is open at one, the upper, end thereof and includes anupper section 77 which has an internal dimension which is substantiallythe same as the outer dimension of the valve stem 7 of the canister 5and a lower section 78 which has a smaller dimension, which sections 77,78 together define an annular seat for the distal end of the valve stem7.

In this embodiment, the stem block 8 includes a lateral cavity 80 whichslidingly receives the nozzle outlet 70 of the mouthpiece 14 and isfluidly connected to the tubular bore 76 thereof. The nozzle outlet 70is configured to be a tight friction fit in the lateral cavity 80 in thestem block 8. Desirably, the tight friction fit provides a gas-tightseal. In other embodiments, other types of sealing method, alsopreferably arranged to provide a gas-tight seal, may be employed.

With this configuration of the stem block assembly 3, the nozzle outlet70 (or the mouthpiece 14) and the stem block 8 (or the lower housingpart 12) can be formed of different materials and to differentspecifications which are specifically suited to their purposes.

FIG. 11 shows a variation 101 of the drug dispenser device of FIGS. 1 to10, with like features being identified with like reference numerals.The device 101 of FIG. 11 is identical to the embodiment of FIGS. 1 to10 in all aspects other than that the dual horizontal slot-like airholes 66 visible in FIG. 10 are replaced by an arrangement of fourcircular air holes 166 (only three visible in FIG. 11) about the sprayorifice 172 at the rear (i.e. base of the ‘bucket’) of the internalsection 117 of the mouthpiece 114. It may be seen that the four airholes 166 are arranged in a generally circular arrangement about thespray orifice 172, in this embodiment being at 90° angular displacementrelative to each other. The spray orifice 172 may be centrally locatedin the circular arrangement of the air holes 166. As may be seen in FIG.11, when external air 160 a is drawn through these plural spaced airholes 166 a plurality of air flows 162 is defined within the mouthpiece114. This provides for an essentially annular air flow at the innerperipheral surface of the mouthpiece 114, which essentially sheaths theaerosol spray 164 as delivered from the spray orifice 172 of the nozzleoutlet 170, thereby entraining the aerosol spray and reducing depositionat the internal surface of the mouthpiece 114.

FIGS. 30a to 30n show other mouthpiece forms 514 a to 514 n, which maybe employed in the drug dispenser device of FIGS. 1 and 11 as analternative to the mouthpieces 14, 114 thereof. These alternativemouthpiece forms 514 a to 514 n differ only in the size, shape andnumber of respective air holes 566 a to 566 n provided to the rear ofthe internal section 517 a to 517 n of these alternative mouthpieceforms 514 a to 514 n, which air holes 566 a to 566 n are as before,arranged about a spray orifice 572 a to 572 n.

Thus, FIGS. 30a to 30d and 30i show different arrangements of fourcircular air holes 566 a to 566 d and 566 i; FIGS. 30e and 30f showdifferent arrangements of three slot-like air holes 566 e, 566 f; FIGS.30g and 30h show different arrangements of six slot-like air holes 566g, 566 h; FIG. 30j shows an arrangement of many circular air holes 566j; FIG. 30k shows an arrangement of six curved slot air holes 566 karranged in two concentric rings; FIGS. 30l to 30n show differentarrangements of three curved slot air holes 566 l to 566 n arranged in aring pattern.

The upper front part 10 a of the drug dispenser device 1, 101 of FIGS. 1and 11 is arranged for receipt and housing of an actuation counter.FIGS. 12 to 18 b provide details of the workings of a suitable actuationcounter. FIGS. 19 to 21 show more details of the interaction of theactuation counter with the actuating mechanism of the drug dispenserdevice 1, 101.

Referring now to FIG. 12, this shows an actuation counter 201 for usewith the drug dispenser device 1, 101 herein. FIGS. 13a and 13brespectively show underside and top views of the actuation counter 201.

The actuation counter 201 is comprised within upper front part 10 a ofthe drug dispenser device 1 (or 101) provided with first 212 and second214 spindle mountings, each capable of defining an axis of rotation anda circumferential wall 218 defining a bezel form retainer 219. A viewingwindow 216 is provided to the housing to enable the viewing of thecount. As will be understood by a comparison of FIG. 1 with FIG. 13b ,the oval-shaped front face 101 of the upper front part 10 a is coveredwith a correspondingly shaped label 103 to cover the apertures in thefront face 101 shown in FIG. 13b , but not the viewing window 216. Inother words, the label has an aperture 105 which registers with theviewing window 216. In an alternative embodiment, the label 103 mayitself have a transparent portion in place of the aperture 105 to enableobservation of the viewing window 216.

Now describing the workings of the actuation counter in more detail:First, disc-shaped count wheel 220 has ‘units’ (i.e. numerals) countindicia 222 provided at spaced intervals on a top face thereof. Thefirst count wheel 220 is provided with a central aperture 226 and acircular cavity 223 that is arranged for disposed receipt of ratchetwheel 250. Ratchet drive receipt teeth 224 are arranged about the innercircumferential wall 225 of the cavity for ratcheted drive interactionwith the ratchet wheel 250. The ratchet wheel 250 itself, is sized andshaped for receipt by the circular cavity 223 of the first count wheeland is provided with two oppositely-located drive tongues 252 a, 252 bfor ratcheted drive interaction with the ratchet drive receipt teeth224. The ratchet wheel 250 is also provided with a drive-receivingprotrusion 254 arranged in use, for drivable rotation of the ratchetwheel 250. As will be described in more detail hereinafter withreference to FIGS. 19 to 21, the drive-receiving protrusion 254 receivesdrive in response to drive interaction with downward drive slot 82provided to front plate 80 in which the drive-receiving protrusion 254is located. The front plate 80 is permanently fixed to the containercollar 30 so as to move in tandem therewith. In this embodiment, thefront plate 80 is permanently fixed to the container collar 30 byultrasonic welding.

Noting that the front plate 80 moves on a linear path (along axis L-L)on actuation of the drug dispenser device 1, 101 and that the ratchetwheel 250 rotates, the drive slot 82 allows for the transverse componentof motion of the drive-receiving protrusion 254 therein as the ratchetwheel 250 rotates upon the drive-receiving protrusion 254 being drivenby the drive slot 82.

Second, ring form count wheel 230 also has ‘tens of units’ (i.e.decimals) count indicia 232 provided at spaced intervals on a top face237 thereof and a set of teeth 234 provided in annular arrangement tothe underside thereof. It may be noted that at stop position 238, acouple of the teeth 234 have been removed and further that the outercircumferential edge of top face 237 is formed with a series of equallyspaced notches or indentations 236. The reasons for these features willbecome clear from the later description. The second count wheel 230 isalso provided with a protruding shutter 280, the function of which willalso be described later.

Kick wheel 240 has kick teeth 244 provided in annular arrangement aroundthe circumference thereof.

As may be best seen at FIG. 13a , when assembled, second count wheel 230is received for rotation within the bezel form retainer 219 of thehousing; and first count wheel 220 is received within the inner ringvoid 235 defined by ring-shaped second count wheel 230 and its centralaperture 226 by first spindle 212 such that clearance exists between thefirst 220 and second 230 count wheels. Thus, the first 220 and second230 count wheels are in concentric relationship, but the level of thesecond count wheel 230 is slightly raised relative to that of the firstcount wheel 220 to enable shutter 280 to protrude over and above thefirst count wheel 220. Ratchet wheel 250 is received within the circularcavity 223 of the first count wheel 220 such that drive tongues 252 a,252 b engage with the ratchet drive receipt teeth 224. Both wheels 220,230 and the ratchet wheel 250 are rotatable about a common first axis ofrotation F-F defined in combination by the axis of first spindle 212 andthe circular shape of the bezel retainer 219. The drive-receivingprotrusion 254 is offset from the first axis F-F, as is the drive slot82. Moreover, the protrusion 254 and drive slot 82 are both offset tothe longitudinal axis L-L.

Kick wheel 240 is received by second spindle 214 for rotation about asecond axis of rotation S-S defined by the second spindle 214 andtherefore offset from the first axis of rotation F-F. It will beappreciated that the second axis of rotation S-S is spaced from thefirst axis of rotation F-F to be outside the path of rotation defined bythe outwardly-facing teeth 234 of the second count wheel 230. Moreover,the first and second axes F-F, S-S are parallel, or substantiallyparallel, to each other.

The set of kick teeth 244 of the kick wheel 240 are in meshedrelationship with the set of teeth 234 of the second count wheel 230such that rotary motion of the kick wheel 240 results in rotary motionof the second count wheel 230. In turn, ratchet drive tongues 252 a, 252b of ratchet wheel 250 mesh with the ratchet drive receipt teeth 224 ofthe first count wheel 220 for drivable rotation of the first count wheel220.

As will be described in more detail hereinafter, when the actuationcounter 201 is disposed in the drug dispenser 1,101, the ratchet wheel250 is in turn drivably rotatable about the first axis F-F by thedrive-receiving interaction of protrusion 254 with downward drive slot82 provided to front plate 80. The front plate 80 fixes to the containercollar 30, which is itself drivable downwards in response to effectiveuser actuation of the drug dispenser device 1, 101.

First count wheel 220 may also be seen to be provided at its peripherywith a pair of fixed index teeth 228 a, 228 b (as may be best seen inFIG. 15a ) arranged for intermittent meshing with the kick teeth 244 ofthe kick wheel 240 such that rotary motion of the kick wheel 240 resultsfrom rotary motion of the first count wheel 220 only when saidintermittent meshing occurs.

In a subtle aspect, it may be seen that the profile of all teeth 234,228 a, 228 b, 244 has a flanged form, which is selected to optimise thevarious toothed engagements necessary for effective gearing andinter-operability of the parts of the counter.

In a further subtle aspect, the counter 201 is arranged to count downfrom ‘120’ to a ‘shuttered position’. The second count wheel 230 isthus, arranged to define fourteen equal pitches allied to twenty-six(calculated as (2×14)−2) teeth 234 plus two missing teeth at stopposition 238. The number of pitches is defined as x+2, wherein x is thehighest numeral on the second count (i.e. decimals) wheel, which in turncorresponds to a highest count of 10 times x (i.e. 10×12=120, in thisembodiment). The ‘+2’ part of the sum determining the number of pitchesrelates to one coloured portion 282 and one shutter portion 280, as aredescribed in more detail later.

Overall, it may be noted that the actuation counter 201 has a relativelycompact form to assist its receipt within the upper front housing part10 a of the drug dispenser device 1, 101. In particular, the counter 201extends upwards in the direction of the axes F-F, S-S to only a minorextent.

Operation of the actuation counter 201 is now described with additionalreference to FIGS. 14a to 16b , in which only the most relevant featuresto the described operation are labelled. The actuation counter 201 isarranged to count down and thus, to illustrate a count operation, FIGS.14a, 15a and 16a show the actuation counter 201 at a ‘count 120’position and FIGS. 14b, 15b and 16b show the actuation counter 201 at a‘count 119’ position (i.e. just after counting down from 120).

It will be appreciated that the ‘count’ of the dose counter 201 referredto herein is the count number collectively presented by the count wheels220, 230 in the window 216.

To initiate a general count operation, ratchet wheel 250 is rotated inresponse to effective user actuation of the drug dispenser device 1, 101by squeezing the levers 20 a, 20 b together as described with referenceto FIGS. 1 to 7 above. This results in the drive slot 82 driving theratchet wheel protrusion 254 to rotate the ratchet wheel 250 in a firstrotary sense (clockwise in FIGS. 12 and 13 a). This, in turn, results inrotation of the first count wheel 220 in the first rotary sense by themeshed interaction of drive tongues 252 a, 252 b with ratchet drivereceipt teeth 224. The ratchet wheel 250 and first count wheel 220 areconfigured and arranged such that when indexed first count wheel 220rotates by 36° such that a single indicium 222 thereon is advanced (i.e.the ‘units’ count moves down one unit).

Where the pre-count operation visible count is x0 (e.g. 120 with ‘x=12’,as shown at FIGS. 14a, 15a and 16a ), the counting action resulting fromthe use operation is subtly different. Once again, ratchet wheel 250 isrotated in response to effective user actuation of the drug dispenserdevice 1, 101 causing rotation of the first count wheel 220 by 36° suchthat the ‘unit’ indicium 222 moves on from ‘0’ to ‘9’ (as shown at FIGS.14b and 15b ). This rotation of the first count wheel 220 however, alsobrings the pair of index teeth 228 a, 228 b into meshed relationshipwith the kick teeth 244 of kick wheel 240 such that the kick wheel 240rotates and in turn, causes the second count wheel 230 to rotate throughmeshing of their respective teeth 234, 244. The wheels 220, 230, 240 areconfigured and arranged such that the resultant rotation of the secondcount wheel 230 is by 360/14° (that is to say by 360/n° wherein n is thenumber of number spacings, where in this case n=14 because there aretwelve decimals indicia 232; one shutter portion 280 and one colouredportion 282) such that a single indicium 232 thereon is advanced (i.e.the ‘tens’ count moves down exactly one unit). In this instance, thedecimal indicium 232 moves down from ‘12’ to ‘11’, as shown in FIGS. 14aand 14 b.

Where the previous visible count was 10 (i.e. x=1), the counting actionresulting from the use operation is again subtly different in that thekick wheel 240 action, as described above, results in the coloured (e.g.red) portion 282 of the second count wheel 230 being advanced into placein the window 216 such that the next display is ‘red 9’ (i.e. colouredportion 282; and numerals indicia 222 is number 9).

As shown at FIGS. 17a and 18a , where the previous visible count was‘red 0’ (i.e. x=0), the counting action resulting from the use operationis still again subtly different in that the kick wheel 240 action, asdescribed above, results in the shutter portion 280 of the second countwheel 230 being advanced into place in the window 216 such that the nextdisplay is fully shuttered off (i.e. no indicia 222, 232 visible at all,as shown at FIGS. 17b and 18b ). Additionally, the stop position 238 inthe set of second count wheel teeth 234 is brought into opposed relationwith the kick teeth 244 whereby the kick teeth 244 and the teeth 234 nolonger mesh. Thus, if the first count wheel 220 continues to rotate,e.g. in response to continued user operation of the drug dispenserdevice 1, 101 into which the actuation counter 201 is incorporated,notwithstanding that all drug doses in the prescribed dosing regime havebeen dispensed (although surplus doses may remain in the canister 5 forpatient administration in accordance with regulatory requirements, asunderstood by the skilled person in the art), the index teeth 228 a, 228b of the first count wheel 220 will still intermittently mesh with thekick teeth 244 to cause the kick wheel 240 to rotate. However, thisrotation of the kick wheel 240 will not be transmitted to the secondcount wheel 230, due to the missing teeth of stop position 238, and theshutter 280 remains in the shuttering position in the window 216 so thatthe underlying ‘units’ indicium 222 remains unseen.

In this embodiment, the second count wheel 230 is integrally formed withthe shutter portion 280.

To further illustrate the countdown display of the counter 201, thereader's attention is drawn to Table 1 below. Table 1 shows thesequential countdown for each of the units (first) and decimals (second)count wheels 220, 230 upon succeeding use operations or actuations ofthe counter 201, and also indicates which of these two count wheels 220,230 indexes to bring the counter 201 to its new counter display. Asshown in Table 1, the first (units) count wheel 220 indexes on eachcounter actuation, whereas the second (decimals) count wheel 230 onlyindexes (through the kick wheel 240 supra) each time the units indicium222 of the first (units) count wheel 220 in the window 216 decrementsfrom ‘0’ to ‘9’. At the end of the countdown, when the display isshuttered, the first count wheel 220 is still free to rotate, underneaththe shutter 280 so as not to be visible, and no further indexing of thesecond count wheel 230 occurs due to the stop position 238 providing fordisengagement of the teeth 234, 244 of the second count wheel 230 andthe kick wheel 240.

TABLE 1 Sequential Decimals Units Indexing of Indexing of Counter WheelWheel Units Decimal Display in Count in Count in Wheel to Wheel toWindow Window Window this Count? this Count? 120 12 0 — — 119 11 9 YesYes 118-110 11 8 to 0 Yes No 109 10 9 Yes Yes 108-100 10 8 to 0 Yes No 99  9 9 Yes Yes  98-90  9 8 to 0 Yes No  89  8 9 Yes Yes  88-80  8 8 to0 Yes No  79  7 9 Yes Yes  78-70  7 8 to 0 Yes No  69  6 9 Yes Yes 68-60  6 8 to 0 Yes No  59  5 9 Yes Yes  58-50  5 8 to 0 Yes No  49  49 Yes Yes  48-40  4 8 to 0 Yes No  39  3 9 Yes Yes  38-30  3 8 to 0 YesNo  29  2 9 Yes Yes  28-20  2 8 to 0 Yes No  19  1 9 Yes Yes  18-10  1 8to 0 Yes No  9 ‘Red’ 9 Yes Yes  8-0 ‘Red’ 8 to 0 Yes No ShutteredShuttered Shuttered Yes Yes

After effective user actuation of the drug dispenser device 1, 101 andregistration of the count, the levers 20 a, 20 b are released to returnto their outward rest position and to allow the container collar 30 toreturn to its rest position. This results in the ratchet wheel 250reversing, to reset it in its starting position for the next countingevent, through interaction of the drive slot 82 with the drive-receivingprotrusion 254.

Thus, the ratchet wheel 250 is adapted to not only rotate in the cavity223 of the first count wheel 220 in the first rotary sense (clockwise asviewed in FIGS. 12 and 13 a), but also to rotate in an opposite, secondrotary sense (anti-clockwise as viewed in FIGS. 12 and 13 a) in thefirst count wheel cavity 223.

However, while rotation of the ratchet wheel 250 in the first rotarysense drivably rotates the first count wheel 220 in the first rotarysense for indexing of the units count 222 in the window 216, rotation ofthe ratchet wheel 250 in the opposite, second rotary sense is relativeto the first count wheel 220; i.e. the first count wheel 220 remainsstationary so that the units indicia 222 in the window 216 remainsunchanged. That is to say, frictional engagement between the respectivewheels 220, 250 does not result in reverse rotation of the first countwheel 220, except for tolerance adjustments as discussed below.

To this end, the first count wheel 220 is provided with a pair ofdiametrically opposed resilient tongues or pawls 227 which co-operatewith a serrated circumferential surface 211 of the first spindle 212 a.The serrated surface 211 comprises plural ratchet teeth 215 with whichthe free ends 227 a of the pawls 227 engage. As the skilled person willunderstand, as the first count wheel 220 is driven by the ratchet wheel250 to rotate in the first sense, the free ends 227 a of the pawls 227ride over the respective ratchet tooth 215 presently engaged with anddrop onto the next adjacent ratchet tooth 215 in the first sense, therebeing a step between adjacent teeth 215. This then indexes the firstcount wheel 220 in its new position, at which the next units indicia 222in the count sequence registers with the window 216. However, the stepbetween the adjacent ratchet teeth 215 prevents the first count wheel220 rotating back in the opposite, second sense as the ratchet wheel 250so rotates as the pawl free ends 227 a cannot pass thereover.

As will also be appreciated by the skilled person, the ratchet teeth 215provide tolerances in the indexing rotation of the first count wheel 220by the ratchet wheel 250. In other words, the first count wheel 220 canbe slightly over-rotated in the first sense, but as the ratchet wheel250 rotates back in the opposite, second sense it carries the firstcount wheel 220 in the same sense, through frictional forces, until thepawl free ends 227 a engage the step between the ratchet teeth 215 whichthen prevents further reverse rotation of the first count wheel 220 andindexes the units indicia 222 in the window 216.

As shown in FIGS. 12 and 13 b, for example, the upper front part 210 ofthe drug dispenser device 1, 201 further provides a resilient pawl 217.The pawl 217 has a free end 217 a which engages the indentations 236 inthe outer circumferential surface of the top face 237 of the secondcount wheel 230, as shown in FIGS. 14a and 14b , for instance. There isone indentation 236 for each count or index position of the second countwheel 230, so the free end 217 a of the pawl 217 and the indentations236 provide an indexing function which provides for accurate alignmentof the decimals indicia 234 in the window 216 and inhibits or preventsreverse rotation of the second count wheel 230.

The indentations 236 in this embodiment have a symmetrical shape, moreparticularly a generally U-shape. However, other shapes could be used.Moreover, asymmetric shapes could also be used. For instance, it may beuseful for the flanks of the indentations 236 to present differentangles, for example for the trailing (rear) flanks of the indentations236 (relative to the direction of rotation of the second count wheel230, e.g. anti-clockwise in FIGS. 14a and 14b ) to form a greater anglewith a central radial line through the indentations 236 than the leading(forward) flanks. This means there is less resistance to the pawl 217releasing from the indentations 236 as the second count wheel 230 isdriven by the kick wheel 240.

It will be appreciated that the above usage of the actuation counter hasbeen described in terms of a counter assembly 201 arranged to countdownwards (i.e. to count on from ‘n+1’ to ‘n’ on indexing), but that thecounter assembly may be straightforwardly modified to count upwards(i.e. instead to count on from ‘n’ to ‘n+1’ on indexing).

The components of the actuation counter 201 and any assemblies andsub-assemblies described above may be made from any suitable materialssuch as plastic polymer materials (e.g. acetal or ABS or styrenepolymers).

In a modification of the counter 201 (not shown), the frictionresistance between the kick wheel 240 and its spindle mounting 214 maybe increased to provide a dragging or braking effect which retards thespeed of rotation of the kick wheel 240 when driven by the first countwheel 220. One possible way to achieve this is through the provision ofaxially-oriented splines about the outer periphery of the spindlemounting 214. This may prevent or inhibit any tendency for the secondcount wheel 230 to be misaligned or over-indexed by a fast moving kickwheel 240.

The interrelationship between the actuation counter 201 and the drugdispenser device 1 is now described in more detail with reference toFIGS. 19 to 21. For clarity and succinctness, only relevant parts ofFIGS. 19 to 21 are labelled.

FIG. 19 shows the drug dispenser device 1 with upper front cover part 10a and actuation counter 201 removed. The device 1 is in the ‘at rest’position with the levers 20 a, 20 b not depressed.

FIG. 20 shows the drug dispenser device 1 with the upper front coverpart 10 a and actuation counter 201 disposed therein shown detached fromthe remainder of the device 1. The drug dispenser device 1 is again inthe at rest′ position with the levers 20 a, 20 b not depressed. FIG. 21shows further details of the actuation counter 201 disposed in the upperfront cover part 10 a of the drug dispenser device 1.

Arrow A of FIG. 20 indicates the direction of movement of the containercollar 30 and front plate 80 attached thereto resulting from effectiveuser actuation of the drug dispenser device. Arrow B of FIG. 20indicates the resulting interaction between the downward drive slot 82of the front plate 80 and the drive-receiving protrusion 254 of theratchet wheel 250 of the actuation counter 201.

Detailed aspects of the drug dispenser device 1 and actuation counter201 of FIGS. 19 to 21 correspond to those already described by referenceto FIGS. 1 to 11 and FIGS. 12 to 18 b respectively, and for succinctnessthese are not described further.

Registration of a count is now described. In use, following effectiveuser actuation of the drug dispenser device 1 by squeezing the levers 20a, 20 b together, as described hereinabove with reference to FIGS. 1 to7, the container collar 30 and front plate 80 move downwards in tandem.The downward drive slot 82 on the front plate 80 drivably engages thedrive-receiving protrusion 254 to drive on the ratchet wheel 250 of theactuation counter thereby resulting in registration of a count. Asdescribed previously, effective user actuation which results in thedownward movement of the container collar 30 (and actuation of drugrelease from the canister 5) occurs only once a pre-load threshold(‘tipping’) force has been overcome (by that effective user actuation).Thus, it will also be appreciated that a count is only registered by theactuation counter 201 in response to such an effective user actuation.The registered count thus, fully ties in with the number of occurrencesof drug release.

FIGS. 22 to 27 c show different aspects of key parts of an alternativeinternal mechanism for use with the drug dispenser device 1 and canister5 as hereinbefore described. This alternative mechanism may beappreciated to be a slight variation of that previously described,mainly in relation to FIG. 5.

Details of the container collar 330 of the alternative internalmechanism are shown at FIGS. 22 and 23. Details of the extension collar340 of the alternative internal mechanism are shown at FIGS. 24 and 25.Assembly steps relating to the alternative internal mechanism areillustrated at FIGS. 26a to 26c , and key operational aspects at FIGS.27a to 27 c.

As before, the container collar 330 permanently engages via split-ringcollar 333 with the neck 305 a of the canister 305 such that theso-engaged parts are moveable together relative to the housing in adirection defined by the longitudinal axis L-L of the canister 305 (i.e.generally up and down when the device 1 is upright). The split-ringcollar 333 permanently engages the container collar 330 to the canister305 as described in U.S. patent application Ser. No. 10/110,611(WO-A-01/28887) and US-A-2006/0082039.

Again, as before the container collar 330 connects via closed coilextension springs 350 a (only one visible in FIG. 26c ) and respectivespring connection points 331 a, 331 b and 341 a, 341 b to extensioncollar 340, which is provided at its lower end with an outer ramp 344,and also with an inner ramp 343. This multi-collar arrangement is suchthat the extension collar 340 is moveable with respect to the containercollar 330 along the longitudinal axis L-L of the drug discharge device.

The extension collar 340 includes an actuating portion in the form ofshelf 342, which is arranged for interaction with the lower ends 21 a,21 b of the opposing levers 20 a, 20 b such that when the levers 20 a,20 b of the device 1 are squeezed together (i.e. inwards relative to thehousing) the shelf 342 and hence, extension collar 340 are pusheddownwards. The container collar 330 is further provided with flexiblesupport legs 334 a, 334 b, 334 c which as before, act to provide apre-load mechanism to prevent transfer of that biasing energy to thecontainer collar 330 to move the canister 5 downwards along thelongitudinal axis L-L to actuate the valve thereof (and hence, to firethe aerosolized drug dose) until a pre-determined threshold force isovercome. Again, as before each flexible support leg 334 a, 334 b, 334 cis arranged for interaction with a respective step 18 a, 18 b on thehousing. However, in this variation each flexible support leg 334 a, 334b, 334 c is provided with a protruding inner foot 335 a, 335 b, 335 cand protruding outer foot 336 a, 336 b (only two visible) the purpose ofwhich will become clearer from the later description.

Assembly steps relating to those key parts of the alternative internalmechanism are illustrated at FIGS. 26a to 26c . The split-ring collar333, which generally comprises a plastic polymer material, is used topermanently fix the container collar 330 to the neck 305 a of thecanister 305 by ultrasonic welding, as generally described in U.S.patent application Set. No. 10/110,611 (WO-A-01/28887) andUS-A-2006/0082039.

The welding process may use two sonotrodes (ultrasonic welding heads)each with three small conical projections to focus the weld energy.During the welding process the conical projections are plunged into theouter surface of the container collar 330 allowing the ultrasonic energyto create a pool of molten material to form the bond (welds) betweeninside surface of the container collar 330 and the outer surface of thesplit-ring collar 333, which is wedged between the neck 305 a of thecontainer 305 and the inside surface of the container collar 330.

In a subtle variation of that ultrasonic welding process, the innersurface of the container collar 330 is provided with plural (e.g. twosets of three) spaced longitudinal ribs (not visible). During thisvariation of the welding process one or more plural pronged (e.g. threepronged) ultrasonic welding heads (not shown) are arranged about thecontainer collar 330 with their prongs aligned one to each rib (whichabut with the split-ring collar 333 which is wedged between thecontainer neck 305 a and the ribs) and ultrasonic energy applied to formwelds between the inside surface of the container collar 330 and theoutside surface of the split-ring collar 333 using the rib material.

This alternative welding process, which is known as an ‘energydeflection’ method avoids any ‘splash back’ of particulate weld materialwhich may otherwise occur where some of the molten material may bedisplaced onto the outside surface of the container collar 330 to form a‘splash’ thereon which can subsequently detach. Such ‘splash back’ isdisadvantageous because any particulates resulting there from maypotentially lodge within the dispenser and thus, possibly be inhaled bythe user. As the alternative process focuses the weld energy at theinternal ribs, the sonotrode(s) no longer has the conical projectionsand, as the ribs are sandwiched between the container collar 330 and thesplit-ring collar 333, most if not all extraneous molten material willbe encapsulated and therefore unable (or less able) to become detached.

As shown at FIG. 26a , in a first step of the assembly process, thecanister 305 with split-ring collar 333 located about its neck 305 a isaligned above the container collar 330 and extension collar 340. In anext step, as shown at FIG. 26b , the canister 305 with split-ringcollar 333 is inserted into the container collar 330, the split-ringcollar 333 is adjusted to be wedged between the neck 305 a and theinside surface of the container collar 330 and then the container collar330 and the split-ring collar 333 are permanently joined by one of theafore-described welding processes to thereby permanently fix thecontainer collar 330 to the canister 305. The so-engaged parts 305, 330,333 are moveable together relative to the housing in a direction definedby the longitudinal axis L-L of the canister 305 (i.e. generally up anddown when the device 1 is upright).

The canister 305 and container collar 330 assembly is then inserted intothe extension collar 340. The container collar 330 is connected viaclosed coil extension springs 350 a (only one visible) and respectivespring connection points 331 a, 331 b and 341 a, 341 b to the extensioncollar 340, as shown at FIG. 26c . When so-connected, the extensioncollar 340 is moveable with respect to the container collar 330 alongthe longitudinal axis L-L of the drug discharge device.

It will be appreciated that the overall form of the alternative internalmechanism is very similar to that previously described in relation toFIG. 5 other than that the shaping of the flexible support legs 334 a,334 b, 334 c differs slightly from those legs 34 a, 34 b of the internalmechanism of FIG. 5, and that correspondingly the ramp 44 thereof isreplaced in the alternative internal mechanism by both an inner 343 andouter 344 ramp. The operational effect of these slight variations isdescribed in greater detail below in relation to FIGS. 27a to 27c .Other than these slight variations, the general principles of operationof the device 1 with the alternative internal mechanism of FIGS. 22 to27 c correspond to those previously described with reference to FIGS. 3ato 4 c.

Thus, in general operational terms, referring now also to FIGS. 27a to27c , the opposing levers 20 a, 20 b of the device 1 are moveabletransversely with respect to the longitudinal axis L-L of the drugdischarge device to apply a force to the shelf 342 of the extensioncollar 340 to move the extension collar 340 downwards along thatlongitudinal axis (i.e. towards stem block 8 and mouthpiece 14 of thedevice 1).

The closed coil extension springs 350 a that connect the containercollar 330 via connector points 331 a, 331 b with the extension collar340 act as a biasing mechanism to store biasing energy on moving theextension collar 340 downwards along the longitudinal axis L-L inresponse to squeezing of the levers 20 a, 20 b. In embodiments, aninitial biasing tension—inherent in the closed coil form thereof—ispresent in the closed coil extension springs 350 a even when in their‘at rest’ state.

The flexible support legs 334 a, 334 b, 334 c act to provide a pre-loadmechanism to prevent transfer of that biasing energy to the containercollar 330 to move the canister 305 downwards along the longitudinalaxis L-L to actuate the valve thereof (and hence, to fire theaerosolized drug dose) until a pre-determined threshold force isovercome.

FIGS. 27a to 27c illustrate details of the relationship between aflexible support leg 334 a of container collar 330 and an inner 343 andouter ramp 344 of the extension collar 340 during operation of thedevice 1.

FIG. 27a shows details of this relationship when the device 1 is in the‘at rest’ position (i.e. corresponding to previous FIG. 3a ). That is tosay, with no downward force applied by the levers 20 a, 20 b to theshelf 342 of the extension collar 340. The flexible support leg 334 a ofthe container collar 330 protrudes down between the inner 343 and outer344 ramps of the extension collar 340, and interacts at its bottom endwith a respective step 18 a, 18 b, 18 c on the housing.

FIG. 27b shows details of this relationship when the device 1 is in a‘tipping point’ configuration (i.e. roughly corresponding to previousFIG. 4c ). In this position, significant downward force has been appliedby the levers 20 a, 20 b of the device 1 to the shelf 342 of theextension collar 340. The outer ramp 344 of the extension collar 340 hasbeen brought down on the protruding outer foot 336 a of the flexible legsupport 334 a, thereby causing the flexible leg support 334 a to flexinwards and to be displaced interiorly to the outer ramp 344. Inconsequence, the container collar 330 may now move freely downwards andindeed, will do so as a result of its experience of biasing energystored in the extension springs 350 a. The container collar 330 andcanister 305 in permanent engagement therewith move rapidly downwardspropelled by the stored biasing energy of the springs 350 a. The valve306 of the canister 305 is thereby activated to release aerosolized drugfor inhalation by the patient.

As before, it will be appreciated that once the threshold force has beenovercome (i.e. just past the ‘tipping point’ of the device 1) a uniformactuating force resulting from the energy stored in the springs 350 a isexperienced by the container collar 330 and canister 305 regardless ofhow much extra force is applied by the patient to the levers 20 a, 20 b.A consistent actuation of the valve of the canister 305 is thereby,enabled.

Following actuation, the coiled coil extension springs 350 a return totheir ‘at rest’ state (i.e. with no externally-applied biasing energy,but only any initial biasing tension inherent in the closed coil form ofthe extension springs 350 a present). As will be appreciated by theskilled reader in the art, the return spring (not shown) of the valve306 of the valved canister provides energy to move the canister 305,container collar 330, extension collar 340 and levers 20 a, 20 b back tothe ‘at rest’ position. As shown at FIG. 27c , during this returnoperation the inner protruding foot 335 a of the flexible leg 334 ainteracts with the inner ramp 343 of the extension collar 340, theeffect of this interaction being to push the flexible leg 334 a outwardsto the ‘at rest’ state of FIG. 27a , in which the flexible leg 334 a isun-flexed.

Where not stated, the components of the drug dispenser devices hereinmay be made from conventional engineering materials, especiallyconventional engineering plastics materials, more especially those whichallow moulding of the component.

Each of the above-described embodiments may be modified to incorporateone or more features disclosed in the U.S. Provisional and/orInternational Applications incorporated herein by reference in thesecond and third paragraphs hereof.

It will be appreciated that the mouthpiece 14 in the exemplaryembodiments could be configured instead as a nasal nozzle for insertionin a nostril of a human being, so that the drug formulation isdeliverable to the nasal cavity of the human being.

The drug dispenser device herein is suitable for dispensing of a drugformulation to a patient. The drug formulation may take any suitableform and include other suitable ingredients such as diluents, solvents,carriers and propellants.

Administration of drug may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment or palliative care. It will be appreciated that the precisedose administered will depend on the age and condition of the patient,the particular drug used and the frequency of administration and willultimately be at the discretion of the attendant physician. Embodimentsare envisaged in which combinations of drugs are employed.

Appropriate drugs may thus be selected from, for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate(e.g. as the sodium salt), ketotifen or nedocromil (e.g. as the sodiumsalt); antiinfectives e.g., cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.,methapyrilene; anti-inflammatories, e.g., beclomethasone (e.g. as thedipropionate ester), fluticasone (e.g. as the propionate ester),flunisolide, budesonide, rofleponide, mometasone e.g. as the furoateester), ciclesonide, triamcinolone (e.g. as the acetonide) or6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (e.g. as free base orsulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), salmefamol, carbuterol, mabuterol,etanterol, naminterol, clenbuterol, flerbuterol, bambuterol,indacaterol, formoterol (e.g. as fumarate), isoprenaline,metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. asacetate), reproterol (e.g. as hydrochloride), rimiterol, terbutaline(e.g. as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoic acid (e.g. as free acid orpotassium salt), diuretics, e.g., amiloride; anticholinergics, e.g.,ipratropium (e.g. as bromide), tiotropium, atropine or oxitropium;hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines,e.g., aminophylline, choline theophyllinate, lysine theophyllinate ortheophylline; therapeutic proteins and peptides, e.g., insulin orglucagon; vaccines, diagnostics, and gene therapies. It will be clear toa person skilled in the art that, where appropriate, the drugs may beused in the form of salts, (e.g., as alkali metal or amine salts or asacid addition salts) or as esters (e.g., lower alkyl esters) or assolvates (e.g., hydrates) to optimise the activity and/or stability ofthe drug.

The drug formulation may in embodiments, be a mono-therapy (i.e. singleactive drug containing) product or it may be a combination therapy (i.e.plural active drugs containing) product.

Suitable drugs or drug components of a combination therapy product aretypically selected from the group consisting of anti-inflammatory agents(for example a corticosteroid or an NSAID), anticholinergic agents (forexample, an M₁, M₂, M₁/M₂ or M₃ receptor antagonist), otherβ₂-adrenoreceptor agonists, antiinfective agents (e.g. an antibiotic oran antiviral), and antihistamines. All suitable combinations areenvisaged.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and 9α,21 dichloro-11β, 17α methyl-1,4pregnadiene 3,20 dione-17-[2′]furoate (mometasone furoate).

Further corticosteroids are described in WO02/088167, WO02/100879,WO02/12265, WO02/12266, WO05/005451, WO05/005452, WO06/072599 andWO06/072600.

Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful are disclosed WO03/082827, WO98/54159, WO04/005229, WO04/009017,WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899,WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294,WO04/026248, WO03/061651, WO03/08277, WO06/000401, WO06/000398 andWO06/015870.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.chemokine antagonists), inhibitors of cytokine synthesis or5-lipoxygenase inhibitors. Examples of iNOS inhibitors include thosedisclosed in WO93/13055, WO98/30537, WO02/50021, WO95/34534 andWO99/62875. Examples of CCR3 inhibitors include those disclosed inWO02/26722.

Suitable bronchodilators are β₂-adrenoreceptor agonists, includingsalmeterol (which may be a racemate or a single enantiomer, such as theR-enantiomer), for instance salmeterol xinafoate, salbutamol (which maybe a racemate or a single enantiomer, such as the R-enantiomer), forinstance salbutamol sulphate or as the free base, formoterol (which maybe a racemate or a single diastereomer, such as the R,R-diastereomer),for instance formoterol fumarate or terbutaline and salts thereof. Othersuitable β₂-adrenoreceptor agonists are3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide,3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide,4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol,4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol,N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide,andN-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine,and5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.Preferably, the β₂-adrenoreceptor agonist is a long actingβ₂-adrenoreceptor agonist (LABA), for example a compound which provideseffective bronchodilation for about 12 hours or longer.

Other β₂-adrenoreceptor agonists include those described in WO02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773,WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 andWO03/042160.

Preferred phosphodiesterase 4 (PDE4) inhibitors are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].

Other suitable drug compounds include:cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) disclosed in U.S. Pat. No. 5,552,438 andits salts, esters, pro-drugs or physical forms; AWD-12-281 from elbion(Hofgen, N. et al. 15th EFMC Int Symp Med Chem (September 6-10,Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 fromChiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitoridentified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl.28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585.

Further compounds are disclosed in WO04/024728, WO04/056823 andWO04/103998, all of Glaxo Group Limited.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compounds,which are antagonists of the M₁ or M₃ receptors, dual antagonists of theM₁/M₃ or M₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors.Exemplary compounds include the alkaloids of the belladonna plants asillustrated by the likes of atropine, scopolamine, homatropine,hyoscyamine; these compounds are normally administered as a salt, beingtertiary amines.

Other suitable anti-cholinergics are muscarinic antagonists, such as(3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octaneiodide,(3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octanebromide,4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide,(1R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-[(phenylmethyl)oxy]ethyl}-8-azoniabicyclo[3.2.1]octanebromide,(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide,(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide,(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide,(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octaneiodide, and(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebromide.

Particularly suitable anticholinergics include ipratropium (e.g. as thebromide), sold under the name Atrovent, oxitropium (e.g. as the bromide)and tiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118. Also ofinterest are revatropate (for example, as the hydrobromide, CAS262586-79-8) and LAS-34273 which is disclosed in WO01/04118, darifenacin(CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under thename Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan),terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS124937-52-6 for the tartrate, sold under the name Detrol), otilonium(for example, as the bromide, CAS 26095-59-0, sold under the nameSpasmomen), trospium chloride (CAS 10405-02-4) and solifenacin (CAS242478-37-1, or CAS 242478-38-2 for the succinate also known as YM-905and sold under the name Vesicare).

Other anticholinergic agents include compounds disclosed in U.S. Ser.No. 60/487,981 and U.S. Ser. No. 60/511,009.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. Examples include ethanolamines, ethylenediamines, andalkylamines. In addition, other first generation antihistamines includethose which can be characterized as based on piperizine andphenothiazines. Second generation antagonists, which are non-sedating,have a similar structure-activity relationship in that they retain thecore ethylene group (the alkylamines) or mimic the tertiary amine groupwith piperizine or piperidine.

Examples of H1 antagonists include, without limitation, amelexanox,astemizole, azatadine, azelastine, acrivastine, brompheniramine,cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine,cyclizine, carebastine, cyproheptadine, carbinoxamine,descarboethoxyloratadine, doxylamine, dimethindene, ebastine,epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen,loratadine, levocabastine, mizolastine, mequitazine, mianserin,noberastine, meclizine, norastemizole, olopatadine, picumast,pyrilamine, promethazine, terfenadine, tripelennamine, temelastine,trimeprazine and triprolidine, particularly cetirizine, levocetirizine,efletirizine and fexofenadine.

Exemplary H1 antagonists are as follows:

Ethanolamines: carbinoxamine maleate, clemastine fumarate,diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines: pyrilamine amleate, tripelennamine HCl, andtripelennamine citrate.

Alkylamines: chlropheniramine and its salts such as the maleate salt,and acrivastine.

Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,cyclizine lactate, meclizine HCl, and cetirizine HCl.

Piperidines: Astemizole, levocabastine HCl, loratadine or itsdescarboethoxy analogue, and terfenadine and fexofenadine hydrochlorideor another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

The drug, or one of the drugs, may be an H3 antagonist (and/or inverseagonist). Examples of H3 antagonists include, for example, thosecompounds disclosed in WO2004/035556 and in WO2006/045416.

Other histamine receptor antagonists which may be used includeantagonists (and/or inverse agonists) of the H4 receptor, for example,the compounds disclosed in Jablonowski et al., J. Med. Chem.46:3957-3960 (2003).

In embodiments, the drug formulation includes one or more of aβ₂-adrenoreceptor agonist, a corticosteroid, a PDE-4 inhibitor and ananti-cholinergic.

Generally, powdered drug particles suitable for delivery to thebronchial or alveolar region of the lung have an aerodynamic diameter ofless than 10 micrometers, preferably from 1-6 micrometers. Other sizedparticles may be used if delivery to other portions of the respiratorytract is desired, such as the nasal cavity, mouth or throat.

The amount of any particular drug or a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof which isrequired to achieve a therapeutic effect will, of course, vary with theparticular compound, the route of administration, the subject undertreatment, and the particular disorder or disease being treated. Thedrugs for treatment of respiratory disorders herein may for example, beadministered by inhalation at a dose of from 0.0005 mg to 10 mg,preferably 0.005 mg to 0.5 mg. The dose range for adult humans isgenerally from 0.0005 mg to 100 mg per day and preferably 0.01 mg to 1.5mg per day.

In one embodiment, the drug is formulated as any suitable aerosolformulation, optionally containing other pharmaceutically acceptableadditive components. In embodiments, the aerosol formulation comprises asuspension of a drug in a propellant. In embodiments, the propellant isa fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

Suitable propellants include, for example, C₁₋₄hydrogen-containingchlorofluorocarbons such as CH₂ClF, CClF₂CHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl and CClF₂CH₃; C₁₋₄hydrogen-containing fluorocarbonssuch as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbonssuch as CF₃CF₃ and CF₃CF₂CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of theabove-identified compounds or mixtures, preferably binary mixtures, withother fluorocarbons or hydrogen-containing chlorofluorocarbons forexample CHClF₂, CH₂F₂ and CF₃CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane (CF₃CH₂F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) or mixtures thereof.

The drug formulations are preferably substantially free ofchlorofluorocarbons such as CCl₃F, CCl₂F₂ and CF₃CCl₃. Preferably, thepropellant is liquefied HFA134a or HFA-227 or mixtures thereof.

The propellant may additionally contain a volatile adjuvant such as asaturated hydrocarbon for example propane, n-butane, liquefied, pentaneand isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations, which arefree or substantially free of volatile adjuvants are preferred. Incertain cases, it may be desirable to include appropriate amounts ofwater, which can be advantageous in modifying the dielectric propertiesof the propellant.

A polar co-solvent such as C₂₋₆ aliphatic alcohols and polyols e.g.ethanol, isopropanol and propylene glycol, preferably ethanol, may beincluded in the drug formulation in the desired amount to improve thedispersion of the formulation, either as the only excipient or inaddition to other excipients such as surfactants. In embodiments, thedrug formulation may contain 0.01 to 5% w/w based on the propellant of apolar co-solvent e.g. ethanol, preferably 0.1 to 5% w/w e.g. about 0.1to 1% w/w. In embodiments herein, the solvent is added in sufficientquantities to solubilise part or all of the drug component, suchformulations being commonly referred to as ‘solution’ aerosol drugformulations.

A surfactant may also be employed in the aerosol formulation. Examplesof conventional surfactants are disclosed in EP-A-372,777. The amount ofsurfactant employed is desirable in the range 0.0001% to 50% weight toweight ratio relative to the drug, in particular, 0.05 to 10% weight toweight ratio.

The aerosol drug formulation desirably contains 0.005-10% w/w,preferably 0.005 to 5% w/w, especially 0.01 to 2% w/w, of drug relativeto the total weight of the formulation.

In another embodiment, the drug is formulated as any suitable fluidformulation, particularly a solution (e.g. aqueous) formulation or asuspension formulation, optionally containing other pharmaceuticallyacceptable additive components.

Suitable formulations (e.g. solution or suspension) may be stabilised(e.g. using hydrochloric acid or sodium hydroxide) by appropriateselection of pH. Typically, the pH will be adjusted to between 4.5 and7.5, preferably between 5.0 and 7.0, especially around 6 to 6.5.

Suitable formulations (e.g. solution or suspension) may comprise one ormore excipients. By the term “excipient”, herein, is meant substantiallyinert materials that are nontoxic and do not interact with othercomponents of a composition in a deleterious manner including, but notlimited to, pharmaceutical grades of carbohydrates, organic andinorganic salts, polymers, amino acids, phospholipids, wetting agents,emulsifiers, surfactants, poloxamers, pluronics, and ion exchangeresins, and combinations thereof.

Suitable carbohydrates include monosaccharides include fructose;disaccharides, such as, but not limited to lactose, and combinations andderivatives thereof; polysaccharides, such as, but not limited to,cellulose and combinations and derivatives thereof; oligosaccharides,such as, but not limited to, dextrins, and combinations and derivativesthereof; polyols, such as but not limited to sorbitol, and combinationsand derivatives thereof.

Suitable organic and inorganic salts include sodium or calciumphosphates, magnesium stearate, and combinations and derivativesthereof.

Suitable polymers include natural biodegradable protein polymers,including, but not limited to, gelatin and combinations and derivativesthereof; natural biodegradable polysaccharide polymers, including, butnot limited to, chitin and starch, crosslinked starch and combinationsand derivatives thereof; semisynthetic biodegradable polymers,including, but not limited to, derivatives of chitosan; and syntheticbiodegradable polymers, including, but not limited to, polyethyleneglycols (PEG), polylactic acid (PLA), synthetic polymers including butnot limited to polyvinyl alcohol and combinations and derivativesthereof;

Suitable amino acids include non-polar amino acids, such as leucine andcombinations and derivatives thereof. Suitable phospholipids includelecithins and combinations and derivatives thereof.

Suitable wetting agents, surfactants and/or emulsifiers include gumacacia, cholesterol, fatty acids including combinations and derivativesthereof. Suitable poloxamers and/or Pluronics include poloxamer 188,Pluronic® F-108, and combinations and derivations thereof. Suitable ionexchange resins include amberlite IR120 and combinations and derivativesthereof;

Suitable solution formulations may comprise a solubilising agent such asa surfactant. Suitable surfactants includeα-[4-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxypoly(oxy-1,2-ethanediyl)polymers including those of the Triton series e.g. Triton X-100, TritonX-114 and Triton X-305 in which the X number is broadly indicative ofthe average number of ethoxy repeating units in the polymer (typicallyaround 7-70, particularly around 7-30 especially around 7-10) and4-(1,1,3,3-tetramethylbutyl)phenol polymers with formaldehyde andoxirane such as those having a relative molecular weight of 3500-5000especially 4000-4700, particularly Tyloxapol. The surfactant istypically employed in a concentration of around 0.5-10%, preferablyaround 2-5% w/w based on weight of formulation.

Suitable solution formulations may also comprise hydroxyl containingorganic co-solvating agents include glycols such as polyethylene glycols(e.g. PEG 200) and propylene glycol; sugars such as dextrose; andethanol. Dextrose and polyethylene glycol (e.g. PEG 200) are preferred,particularly dextrose. Propylene glycol is preferably used in an amountof no more than 20%, especially no more than 10% and is most preferablyavoided altogether. Ethanol is preferably avoided. The hydroxylcontaining organic co-solvating agents are typically employed at aconcentration of 0.1-20% e.g. 0.5-10%, e.g. around 1-5% w/w based onweight of formulation.

Suitable solution formulations may also comprise solublising agents suchas polysorbate, glycerine, benzyl alcohol, polyoxyethylene castor oilsderivatives, polyethylene glycol and polyoxyethylene alkyl ethers (e.g.Cremophors, Brij).

Suitable solution formulations may also comprise one or more of thefollowing components: viscosity enhancing agents; preservatives; andisotonicity adjusting agents.

Suitable viscosity enhancing agents include carboxymethylcellulose,veegum, tragacanth, bentonite, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, poloxamers (e.g.poloxamer 407), polyethylene glycols, alginates xanthym gums,carageenans and carbopols.

Suitable preservatives include quaternary ammonium compounds (e.g.benzalkonium chloride, benzethonium chloride, cetrimide andcetylpyridinium chloride), mercurial agents (e.g. phenylmercuricnitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g.chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterialesters (e.g. esters of para-hydroxybenzoic acid), chelating agents suchas disodium edetate (EDTA) and other anti-microbial agents such aschlorhexidine, chlorocresol, sorbic acid and its salts and polymyxin.

Suitable isotonicity adjusting agents act such as to achieve isotonicitywith body fluids (e.g. fluids of the nasal cavity), resulting in reducedlevels of irritancy associated with many nasal formulations. Examples ofsuitable isotonicity adjusting agents are sodium chloride, dextrose andcalcium chloride.

Suitable suspension formulations comprise an aqueous suspension ofparticulate drug and optionally suspending agents, preservatives,wetting agents or isotonicity adjusting agents.

Suitable suspending agents include carboxymethylcellulose, veegum,tragacanth, bentonite, methylcellulose and polyethylene glycols.

Suitable wetting agents function to wet the particles of drug tofacilitate dispersion thereof in the aqueous phase of the composition.Examples of wetting agents that can be used are fatty alcohols, estersand ethers. Preferably, the wetting agent is a hydrophilic, non-ionicsurfactant, most preferably polyoxyethylene (20) sorbitan monooleate(supplied as the branded product Polysorbate 80).

Suitable preservatives and isotonicity adjusting agents are as describedabove in relation to solution formulations.

The drug dispenser device herein is in one embodiment suitable fordispensing aerosolized drug (e.g. for inhalation via the mouth) for thetreatment of respiratory disorders such as disorders of the lungs andbronchial tracts including asthma and chronic obstructive pulmonarydisorder (COPD). In another embodiment, the invention is suitable fordispensing aerosolized drug (e.g. for inhalation via the mouth) for thetreatment of a condition requiring treatment by the systemic circulationof drug, for example migraine, diabetes, pain relief e.g. inhaledmorphine.

Administration of drug in aerosolized form may be indicated for thetreatment of mild, moderate or severe acute or chronic symptoms or forprophylactic treatment. It will be appreciated that the precise doseadministered will depend on the age and condition of the patient, theparticular particulate drug used and the frequency of administration andwill ultimately be at the discretion of the attendant physician. Whencombinations of drugs are employed the dose of each component of thecombination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1, 2, 3 or 4aerosol puffs each time. Each valve actuation, for example, may deliver5 μg, 50 μg, 100 μg, 200 μg or 250 μg of a drug. Typically, each filledcanister for use in a metered dose inhaler contains 60, 100, 120 or 200metered doses or puffs of drug; the dosage of each drug is either knownor readily ascertainable by those skilled in the art.

In another embodiment, the drug dispenser device herein is suitable fordispensing fluid drug formulations for the treatment of inflammatoryand/or allergic conditions of the nasal passages such as rhinitis e.g.seasonal and perennial rhinitis as well as other local inflammatoryconditions such as asthma, COPD and dermatitis. A suitable dosing regimewould be for the patient to inhale slowly through the nose subsequent tothe nasal cavity being cleared. During inhalation the formulation wouldbe applied to one nostril while the other is manually compressed. Thisprocedure would then be repeated for the other nostril. Typically, oneor two inhalations per nostril would be administered by the aboveprocedure up to three times each day, ideally once daily. Each dose, forexample, may deliver 5 μg, 50 μg, 100 μg, 200 μg or 250 μg of activedrug. The precise dosage is either known or readily ascertainable bythose skilled in the art.

In another aspect, the drug dispenser device herein is suitable fordispensing fluid drug formulations for the treatment of inflammatoryand/or allergic conditions of the nasal passages such as rhinitis e.g.seasonal and perennial rhinitis as well as other local inflammatoryconditions such as asthma, COPD and dermatitis. A suitable dosing regimewould be for the patient to inhale slowly through the nose subsequent tothe nasal cavity being cleared. During inhalation the formulation wouldbe applied to one nostril while the other is manually compressed. Thisprocedure would then be repeated for the other nostril. Typically, oneor two inhalations per nostril would be administered by the aboveprocedure up to three times each day, ideally once daily. Each dose, forexample, may deliver 5 μg, 50 μg, 100 μg, 200 μg or 250 μg of activedrug. The precise dosage is either known or readily ascertainable bythose skilled in the art.

It will be understood that the present invention has been describedabove by way of example only and that the above description can bemodified in many different ways without departing from the scope of theinvention as defined by the appended claims.

All publications, patents, and patent applications cited herein, and anyUS patent family equivalent to any such patent or patent application,are hereby incorporated herein by reference to their entirety to thesame extent as if each publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

It must be noted that, as used in the specification and appended claims,the singular forms “a”, “an”, “the” and “one” include plural referentsunless the content clearly dictates otherwise.

What is claimed is:
 1. A drug dispenser device for delivery of a drug byinhalation comprising (a) a housing defining a first chamber; (b)extending from said housing and defining a second open chamber, anoutlet for insertion into a body cavity of a patient; (c) provided tosaid first chamber of the housing, a discharge block defining adischarge block orifice; (d) receivable within the first chamber formovement therewithin, a drug discharge device, wherein the drugdischarge device is suitable for discharging aerosolized drug andcomprises an aerosol canister for storing a drug formulation to bedispensed, provided with a discharge valve having a valve stem, saiddrug discharge device having a longitudinal axis, wherein said valvestem is receivable by said discharge block to enable discharge of saiddrug formulation via said discharge block orifice to said outlet; and(e) provided to the housing, at least one finger operable membermoveable to apply a force directly or indirectly to the drug dischargedevice for movement along the longitudinal axis towards the dischargeblock to actuate said discharge valve, wherein said housing furtherdefines an aperture through which said at least one finger operablemember in part protrudes, and wherein the at least one finger operablemember is moveable from a rest position in which the at least one fingeroperable member acts to block off said aperture to an actuating positionin which the aperture is unblocked and through which air may be drawninto the housing in response to patient inhalation through the outlet,wherein the at least one finger operable member comprises two opposinglevers, each of which pivotally connects to part of the housing andwhich are arranged to actuate the drug dispenser device when the twoopposing levers are squeezed together by a user.
 2. A drug dispenserdevice according to claim 1, wherein the housing is sized and shaped toenable one-handed operation of the dispenser device.
 3. A drug dispenserdevice according to claim 1, wherein the outlet is provided with aremovable protective cover.
 4. A drug dispenser device according toclaim 1, wherein the aerosol canister has a cylindrical form and thelongitudinal axis is defined by the central axis of the cylindricalaerosol canister.
 5. A drug dispenser device according to claim 1,wherein the valve stem extends out from a neck of the aerosol canister.6. A drug dispenser device according to claim 1, wherein the outletincludes at least one air flow path which provides for a substantiallyannular air flow at an inner peripheral surface of the outlet on patientinhalation through the outlet providing a sheathing air flow thereat. 7.A drug dispenser device according to claim 6, wherein a circulararrangement of plural air flow paths is provided.
 8. A drug dispenserdevice according to claim 1, wherein the discharge block comprises, as aseparately-formed component, a discharge outlet which fluidly connectsto the discharge block orifice of the discharge block and includes adischarge outlet orifice from which drug is in use delivered.
 9. A drugdispenser device according to claim 8, wherein the discharge outlet isintegrally formed with the outlet.
 10. A drug dispenser device accordingto claim 8, wherein the discharge outlet is coupled to the outlet.
 11. Adrug dispenser device according to claim 8, wherein, the discharge blockincludes a laterally-directed cavity which receives the dischargeoutlet.
 12. A drug dispenser device according to claim 11, wherein thedischarge outlet is held captive in the laterally-directed cavity bymeans of a press-fit or snap-fit connection.
 13. A drug dispenser deviceaccording to claim 8, wherein at least a rear section of the dischargeoutlet has an increasing internal dimension in a direction away from thedischarge block.
 14. A drug dispenser device according to claim 13,wherein the discharge outlet defines an essentially cone-shapedinterior.
 15. A drug dispenser device according to claim 13, wherein thedischarge outlet defines an essentially bucket-shaped interior.
 16. Adrug dispenser device according to claim 8, wherein the discharge outletincludes a delivery channel which fluidly connects to the dischargeoutlet orifice and narrows towards the same.
 17. A drug dispenser deviceaccording to claim 16, wherein the delivery channel has arcuate wallsections.
 18. A drug dispenser device according to claim 16, wherein thedelivery channel has substantially straight wall sections.
 19. A drugdispenser device according to claim 1, wherein the at least one fingeroperable member is moveable transversely with respect to thelongitudinal axis of the drug discharge device.
 20. A drug dispenserdevice according to claim 1, wherein the at least one finger operablemember is arranged to apply mechanical advantage.
 21. A drug dispenserdevice according to claim 20, wherein said mechanical advantage has aratio of from 1.5:1 to 10:1.
 22. A drug dispenser device according toclaim 1, wherein said two opposing levers are coupled to each other by acoupling mechanism.
 23. A drug dispenser device according to claim 22,said coupling mechanism comprises meshing teeth provided to each of thetwo opposing levers.
 24. A drug dispenser device according to claim 1,wherein the each lever is pivotally supported at a lower end of thehousing.
 25. A drug dispenser device according to claim 1, wherein theat least one finger operable member is biased towards the rest positionthereof.
 26. A drug dispenser device according to claim 1, wherein inthe actuating position a portion of the at least one finger operablemember engages the base of the aerosol canister of the drug dischargedevice to push the aerosol canister towards the discharge block inactuating fashion.
 27. A drug dispenser device according to claim 1,wherein in the actuating position a portion of the at least one fingeroperable member engages an actuating mechanism capable of transferringforce to the aerosol canister of the drug discharge device to push orpull the aerosol canister towards the discharge block in actuatingfashion.
 28. A drug dispenser device according to claim 27, additionallycomprising (f) connecting to the aerosol canister, a container collarthat engages the aerosol canister; (g) connecting to said containercollar and moveable with respect thereto along the longitudinal axis ofthe drug discharge device, a transfer element, said transfer elementincluding an actuating portion, wherein the at least one finger operablemember is moveable to apply a force to said actuating portion of saidtransfer element to move the transfer element along the longitudinalaxis in a first direction; (h) connecting the container collar with thetransfer element, a biasing mechanism to store biasing energy on movingthe transfer element along the longitudinal axis in the first direction;and (i) provided to the container collar, a pre-load mechanism toprevent transfer of said biasing energy to the container collar to movesaid aerosol canister along the longitudinal axis in the first directionto actuate the discharge valve until a pre-determined threshold force isovercome.
 29. A drug dispenser device according to claim 1, additionallycomprising a locking mechanism for reversibly locking the movement ofthe at least one finger operable member.
 30. A drug dispenser deviceaccording to claim 1, wherein the aerosol canister comprises an aerosoldrug formulation comprising a drug in a propellant.
 31. A drug dispenserdevice according to claim 30, wherein said propellant is a fluorocarbonor hydrogen-containing chlorofluorocarbon propellant.
 32. A drugdispenser device according to claim 1, wherein the drug is ananti-inflammatory agent.
 33. A drug dispenser device according to claim32, wherein said anti-inflammatory agent is selected from the groupconsisting of a corticosteroid, an non-steroidal anti-inflammatory(NSAID) drug, a glucocorticoid compound and mixtures thereof.